Once the eosinophil count has normalized and symptoms have improved, the steroid dose should be tapered slowly with a goal of 10 mg prednisone equivalent or less daily. Cardiac response was evaluated at a central laboratory. FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenib. Treatment of hypereosinophilic syndromes—the first 100 years. Patients with aggressive disease and molecular or cytogenetic abnormalities that are typically resistant to steroid and imatinib therapy, including FGFR1 mutations, represent a special category of PDGFR-negative M-HES and should be considered early for alternative therapies. 6q- is an early and persistent chromosomal aberration in CD3-CD4+ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome. 2-Chlorodeoxyadenosine and cytarabine combination therapy for idiopathic hypereosinophilic syndrome. Renal progression was defined as at least a 25% decrease in estimated glomerular filtration rate. Development of assays to detect serum FLC levels allows measurement of hematologic responses in most patients, and the absolute depth of FLC response is now known to affect patient outcomes.43,44  Although negative serum and urine IFE remain requirements for achievement of aCR, investigators have begun to consider the absolute dFLC or iFLC levels a more relevant measure of hematologic response. Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Cardiac and renal response rates in the ANDROMEDA safety run-in cohort were 53% and 83%, respectively, and compare favorably with the current standard nontransplant regimens presented here. Treatment of FIP1L1/PDGFRA-negative hypereosinophilic syndrome with alemtuzumab, an anti-CD52 antibody. Although the presence of clinical features and/or genetic abnormalities consistent with an eosinophilic myeloproliferative disorder precludes a diagnosis of HEUS, abnormal or clonal lymphocyte populations have been described in some patients with HEUS and do not appear to be associated with disease progression.50  A family history should be elicited in all suspected cases of HEUS (see above). HE can occur in the setting of a wide variety of immunologic disorders, particularly those characterized by dysregulation of lymphocyte proliferation or function. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Here we present for the first time the use of the subcutaneous formulation of daratumumab (DARA SC) in AL amyloidosis in the safety run-in cohort of the phase 3 ANDROMEDA study (AMY3001; ClinicalTrials.gov identifier: NCT03201965). Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Immunoglobulin heavy chain expression was observed in 10 patients (8 [30%] IgG and 2 [7%] IgA). DARA SC was administered in a single, premixed vial and given by manual SC injection over the course of 3 to 5 minutes weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter as monotherapy for a maximum of 2 years from study start (all cycles were 28 days). The most common any-grade and grade 3/4 TEAEs are reported in Table 2. Patients received a median of 16 (range, 1-23) treatment cycles with a median duration of treatment of 15.1 (range, 0.2-20.1) months. Median time from diagnosis was 59.5 (range, 15-501) days. Preliminary efficacy was robust, with high rates of deep and durable hematologic responses, and importantly, organ responses elicited by DARA SC plus CyBorD. Apropos of 7 cases]. Efficacy of ruxolitinib in chronic eosinophilic leukemia associated with a PCM1-JAK2 fusion gene. The spectrum of FIP1L1-PDGFRA-associated chronic eosinophilic leukemia: new insights based on a survey of 44 cases [published online ahead of print August 26, 2013]. received an honorarium from Sebia, served on an advisory board for Janssen, and received a travel grant from Celgene. Labs revealed a leukocytosis of 15.7 × 109/L with 51% eosinophils (AEC, 8.0 × 109/L). Conversely, cyclophosphamide is effective in eosinophilic vasculitis13  but would not be the treatment of choice for a patient with PDGFRA-associated MPN. An additional methodologic advance to assess and manage patients with AL amyloidosis is evaluation of minimal residual disease, as the absence of minimal residual disease may be associated with deeper organ response.51, Definitions of deep hematologic responses in AL amyloidosis are evolving. R.L.C. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. 1,2 Frequent causes include atopic disease, asthma, drug hypersensitivity, and helminth infection. Other secondary endpoints included organ response rate (assessed by biomarkers), progression-free survival, OS, improvement in patient-reported fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, time to next treatment, rate of hematologic VGPR or better, time to hematologic and organ response, and duration of organ response. Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study. Amy D. Klion; How I treat hypereosinophilic syndromes. This definition both differs from and overlaps with the current WHO guidelines, which categorize patients with myeloid and lymphoid neoplasms, including those with HES, on the basis of molecular, genetic, histopathologic, and selected clinical criteria.29  As such, patients with HES and myeloproliferative features may be classified among myeloid neoplasms (CEL-NOS, myeloid neoplasms associated with PDGFRA, PDGFRB, or FGFR1, atypical chronic myeloid leukemia), myeloproliferative disorders (myeloproliferative neoplasms unclassifiable, systemic mastocytosis with eosinophilia), or as idiopathic HES (supplemental Table 1). Analysis of SARS-CoV-2-specific adaptive immune responses during acute COVID-19 identifies coordination between SARS-CoV-2-specific CD4 T cells and CD8 T cells to limit disease severity. OKT3 is a monoclonal antibody that inhibits CD3 on T cells. Among the 4 patients with hepatic involvement, 2 showed a response. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Haematologica. The above-described definition of M-HES is based predominantly on clinical and laboratory features that predict treatment response and prognosis within the broader context of patients presenting with HES (AEC of ≥1.5 × 109/L and clinical manifestations attributable to eosinophilia or tissue HE with blood eosinophilia). Estimated glomerular filtration rate, as determined by the Chronic Kidney Disease Epidemiology Collaboration equation, was required to be at least 20 mL/min/1.73 m2. Successful use of nilotinib as primary therapy for M-HES has been reported in one case series,72  and both nilotinib and dasatinib have been used as salvage therapy in isolated patients with PDGFRA-associated MPN who were intolerant to imatinib.73,74  Sorafenib has been used in 2 patients with the imatinib-resistant T674I mutation with transient response,67,69  although outgrowth of a D842V-positive clone occurred in 1 case, ultimately leading to death of the patient.67  The use of other TKIs for imatinib resistant M-HES has not been reported to date. Mild blood eosinophilia, as defined by an absolute eosinophil count (AEC) between 0.5 and 1.0 × 109/L, is common, occurring in 3% to 10% of individuals depending on the population studied.1,2  Frequent causes include atopic disease, asthma, drug hypersensitivity, and helminth infection. Blood 2020; 136 (1): 71–80. Signs and symptoms attributable to the eosinophilia may or may not be present and can be difficult at times to distinguish from manifestations of the underlying disorder. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. In this trial, we assessed 5 patients as achieving mCR, defined as a negative serum and urine IFE and iFLC less than the upper limit of normal, regardless of the uFLC level or FLC ratio. served in a consulting or advisory role for Celgene and Amgen and received research support from AbbVie, Amgen, Janssen, and Prothena. Age-related amyloidosis and hereditary amyloidosis were ruled out, respectively, in male patients at least 70 years of age with cardiac involvement only, and in patients of African descent, using mass spectrometry typing of amyloid deposits in a tissue biopsy. The online version of this article contains a data supplement. Medicine (Baltimore). The online version of this article contains a data supplement. No new safety concerns were identified with DARA SC plus CyBorD compared with daratumumab monotherapy (IV or SC) or CyBorD alone.46-50  DARA SC is associated with low rates of IRRs, few injection-site reactions, and reduced administration times compared with DARA IV.48  The advantages of DARA SC as reported in the phase 3 COLUMBA study in MM,48  particularly the small administration volume, are relevant to patients with AL amyloidosis for whom volume overload is a concern because of cardiac involvement. The majority (n = 22 [79%]) of patients were classified as cardiac stage II or higher per the modified Mayo staging system.39  One patient with values corresponding to stage IIIa during screening subsequently increased to IIIb on cycle 1 day 1. DARA SC plus CyBorD achieved a stringent dFLC response in 68% of patients compared with 30% with bortezomib-based combinations (95% received CyBorD).44  Hematologic responses in the safety run-in cohort of ANDROMEDA compare favorably to all commonly used frontline regimens, including HDM and ASCT. These investigators also showed that an absolute iFLC level of 20 mg/L or less is associated with improved survival.43  Manwani et al recently reported outcomes of patients with newly diagnosed AL (N = 915) treated with bortezomib-based therapy (95% received CyBorD), using a dFLC level lower than 10 mg/L as a “stringent dFLC response.” Achieving a stringent dFLC response was associated with improved OS and time to next treatment compared with less deep responses. After promising results in pilot studies, a double-blind, placebo-controlled trial in 85 PDGFRA-negative patients demonstrated that monthly mepolizumab was safe and effective as a steroid-sparing agent in HES, including L-HES.92,93  Long-term safety and efficacy was confirmed in a second study.92  Mepolizumab is currently available only on clinical protocols for patients with life-threatening HES refractory to standard therapies (as in the case presented) or with EGPA (http://www.clinicaltrials.gov). The relative frequencies of these variants in the general population are difficult to ascertain due in large part to the lack of universally accepted definitions of HES and referral bias (ie, a hematologist is more likely to see M-HES). All patients in the safety run-in cohort received DARA SC (1800 mg in 15 mL) with recombinant human hyaluronidase PH20 (rHuPH20; 30 000 U; ENHANZE drug delivery technology; Halozyme, Inc). Twenty-two (79%) patients had measurable disease, as indicated by serum FLC levels only, and 3 (11%) patients each had disease as measured by serum M-protein levels only and by both serum M-protein and FLC levels. This form of capillary leak syndrome, or cytokine release syndrome, is characterized by the onset of symptoms minutes to hours after the monoclonal antibody has been administered. At this time, the most commonly used front-line regimens for this disease are CyBorD,7  melphalan with dexamethasone,52  and high-dose melphalan (HDM) with ASCT, although the latter is not feasible for many patients with AL amyloidosis.9-11  In patients with newly diagnosed AL amyloidosis receiving CyBorD,7  melphalan with dexamethasone,52  and HDM with ASCT,9-11  hematologic CR rates were 23%, 12%, and 34% to 48%, respectively. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. Here we report the results of the safety run-in phase, which was conducted to determine the safety and tolerability of DARA SC plus CyBorD in at least 10 patients with newly diagnosed AL amyloidosis.
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