Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment.

Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.

Hypomethylating agent monotherapy in core binding factor acute myeloid leukemia: a French multicentric retrospective study.

Very few data are available about hypomethylating agent (HMA) efficiency in core binding factor acute myeloid leukemias (CBF-AML). Our main objective was to evaluate the efficacy and safety of HMA in the specific subset of CBF-AML. Here, we report the results of a multicenter retrospective French study about efficacy of HMA monotherapy, used frontline or for R/R CBF-AML. Forty-nine patients were included, and received a median of 5 courses of azacitidine (n = 46) or decitabine (n = 3). ORR was 49% for the whole cohort with a median time to response of 112 days. After a median follow-up of 72.3 months, median OS for the total cohort was 10.6 months. In multivariate analysis, hematological relapse of CBF-AML at HMA initiation was significantly associated with a poorer OS (HR: 2.13; 95%CI: 1.04-4.36; p = 0.038). Responders had a significantly improved OS (1-year OS: 75%) compared to non-responders (1-year OS: 15.3%; p < 0.0001). Hematological improvement occurred for respectively 28%, 33% and 48% for patients who were red blood cell or platelet transfusion-dependent, or who experienced grade 3/4 neutropenia at HMA initiation. Adverse events were consistent with the known safety profile of HMA. Our study highlights that HMA is a well-tolerated therapeutic option with moderate clinical activity for R/R CBF-AML and for patients who cannot handle intensive chemotherapy.

Extreme thrombocytosis with an aggressive evolution harboring a novel variant of calreticulin (CALR) in exon 3.

We describe the case of a patient with extreme thrombocytosis whose evolution was rapidly fatal. No cause of secondary thrombocytosis was found. There was no sign of myelofibrosis but the megakaryocytes were small and dysplastic. The patient presented a calreticulin (CALR) variant in exon 3 (C105S), as well as concomitant mutations of ASXL1, U2AF1, and EZH2. This variant of CALR has never been described before, and after sorting, all identified mutations were found in myeloid cells but not in lymphoid cells. Therefore, the diagnosis of a frontier case of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) was made. A treatment with hydroxycarbamide was started because of a high risk of thrombosis. Upon worsening of the hematological status two new mutations appeared, SETBP1 and ETV6, and the CALR mutation was still detectable, as well as the three other mutations found in the chronic stage. Our results show that this variant could contribute to MDS/MPN pathogenesis in that patient.

Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT.

Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16-2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09-2.23]) and FluBu9.6 (HR: 1.63 [1.02-2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning.

Anatomic Variation of Sacral Mesh Attachment During Minimally Invasive Sacrocolpopexy.

IMPORTANCE: Although anatomic level of mesh attachment to the sacrum varied during minimally invasive sacrocolpopexy with a large proportion above S1, this was not associated with pelvic organ prolapse recurrence. OBJECTIVE: This study aimed to describe the anatomic level of sacral mesh attachment and its association with prolapse recurrence after minimally invasive sacrocolpopexy. STUDY DESIGN: This study included a retrospective cohort of women who underwent minimally invasive sacrocolpopexy with subsequent abdominal and pelvic imaging (magnetic resonance imaging or computed tomography) between 2010 and 2019 at a single academic institution. Anatomic level of attachment was determined by a radiologist. Prolapse recurrence was defined as a composite of self-reported bulge symptoms, any prolapse measure beyond the hymen, and any retreatment with pessary or surgery. χ 2 Tests were used for comparative outcomes. RESULTS: Analyses included 212 women. The mean ± SD age was 58.8 ± 9.9 years, the majority have preoperative stage III/IV prolapse (81.1%), and the median follow-up was 269 days (interquartile range, 57-825 days). Mesh was attached using titanium tacks (n = 136 [64.2%]) and suture (n = 76 [35.8%]) at the level of the L5-S1 intervertebral space (n = 113 [53.3%]) or overlying S1 (n = 89 [42.0%]).The surgical approach was significantly associated with attachment location with a greater proportion of laparoscopy cases demonstrating mesh attachment above S1 (85 [62.5%] vs robotically, 30 [39.5%]; P < 0.01). Dichotomized level of attachment was not associated with composite prolapse recurrence (above S1, n = 18 [22.2%] vs below S1, n = 24 [24.7%]; P = 0.69) or any compartment recurrence ( P ≥ 0.36). CONCLUSIONS: Mesh was primarily attached to the anterior longitudinal ligament at the level of the L5-S1 intervertebral space or S1. Level of mesh attachment was not associated with composite prolapse recurrence.

Encapsulated Papillary Carcinoma of the Breast: Imaging Features with Histopathologic Correlation.

Encapsulated papillary carcinoma (EPC) is a rare, clinically indolent breast malignancy most common in postmenopausal women. Absence of myoepithelial cells at the periphery is a characteristic feature. Mammographically, EPC typically presents as a mostly circumscribed, noncalcified, dense mass that can have focally indistinct margins when there is associated frank invasive carcinoma. Ultrasound shows a circumscribed solid or complex cystic and solid mass, and occasional hemorrhage in the cystic component may produce a fluid-debris level; the solid components typically show intense washout enhancement on MRI. Color Doppler may demonstrate a prominent vascular pedicle and blood flow within solid papillary fronds. Encapsulated papillary carcinoma can exist in pure form; however, EPC is often associated with conventional ductal carcinoma in-situ and/or invasive ductal carcinoma, no special type. Adjacent in-situ and invasive disease may be only focally present at the periphery of EPC and potentially unsampled at core-needle biopsy. In order to facilitate diagnosis, the mass wall should be included on core-needle biopsy, which will show absence of myoepithelial markers. Staging and prognosis are determined by any associated frankly invasive component, with usually excellent long-term survival and rare distant metastases.

Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: A prospective cohort.

OBJECTIVES: Antibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy. METHODS: Based on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017. RESULTS: Antibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24-30). Antibiotics were started at day 9 (IQR 5-13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7-16) vs. 19 days (IQR 15-23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3-7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2-8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia. CONCLUSIONS: Discontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing.

False-positive technetium-99m methylene diphosphonate bone scan activity in the orbit in a patient with a history of breast carcinoma.

Metastasis of breast carcinoma to the orbit is an uncommon entity and carries a poor prognosis. This case report presents false-positive technetium-99m methylene diphosphonate activity in the right orbit of a patient with a history of a primary breast neoplasm. Orbital computed tomography imaging was obtained to further characterize the radiotracer uptake identified on the bone scan and demonstrated diffuse right globe intraocular calcifications secondary to degenerative intraocular changes. A brief literature review of orbital metastasis from breast carcinoma and causes of intraocular calcification in the context of chronic vision loss are provided.

Diagnostic Accuracy of Digital Breast Tomosynthesis in the Evaluation of Palpable Breast Abnormalities.

RATIONALE AND OBJECTIVES: The role of digital breast tomosynthesis (DBT) in evaluating palpable abnormalities has not been evaluated and its accuracy compared to 2D mammography is unknown. The purpose of this study was to evaluate combined 2D mammography, DBT, and ultrasound (US) at palpable sites. MATERIALS AND METHODS: Two breast imagers reviewed blinded consecutive cases with combined 2D mammograms and DBT examinations performed for palpable complaints. By consensus, 2D and DBT findings were recorded and compared to US. Patient characteristics, demographics, subsequent workup, and outcome were recorded. RESULTS: A total of 229 sites in 188 patients were included, with 50 biopsies performed identifying 18 cancers. All 18 cancers were identified on 2D and US, whereas 17 cancers were identified on DBT. Cancer detection sensitivities for 2D, DBT, and US were 100.0%, 94.4%, and 100.0%. The negative predictive value, when combined with US, was 100% for both. The sensitivity and the specificity for both benign and malignant findings with 2D and DBT were 70.5% versus 75.4% (P = 0.07) and 95.3% versus 99.1% (P = 0.125). Palpable findings not identified by 2D and DBT were smaller than those identified (11.5 ± 8.3 mm vs 23.9 ± 12.8 mm, P < 0.001). Patients with dense breasts were more likely to have mammographically occult findings than patients with nondense breasts (27.4% vs 8.3%). CONCLUSIONS: DBT did not improve cancer detection over 2D or US. Both mammographic modalities failed to identify sonographically confirmed findings primarily in dense breasts. The diagnostic use of DBT at palpable sites provided limited benefit over combined 2D and US. When utilizing DBT, US should be performed to adequately characterize palpable sites.

IgMκ and IgMλ Measurements for the Assessment of Patients with Waldenström's Macroglobulinaemia.

PURPOSE: Accurate quantification of monoclonal IgM immunoglobulins is essential for response assessment in patients with Waldenström's macroglobulinaemia (WM). The propensity of IgM to form multimers in serum makes sample evaluation by current laboratory methods particularly challenging. EXPERIMENTAL DESIGN: We assessed the precision and linearity of IgMκ and IgMλ heavy/light chain (HLC, Hevylite) assays, and established reference intervals using 120 normal donor sera. We compared the quantitative performance of HLC assays with serum protein electrophoresis (SPE) and total IgM nephelometry for 78 diagnostic samples and follow-up samples from 25 patients with WM. Comparisons were made between the three methods for diagnostic sensitivity and response assessment. RESULTS: IgMκ and IgMλ HLC assays showed low imprecision and good linearity. There was good agreement between summated HLC (IgMκ + IgMλ) and total IgM (measured nephelometrically; R2 = 0.90), but only moderate agreement between involved IgM HLC and SPE densitometry (R2 = 0.49). Analysis of 120 normal donor sera produced the following normal ranges: IgMκ: 0.29-1.82 g/L; IgMλ: 0.17-0.94 g/L; IgMκ/IgMλ ratio: 0.96-2.30. Using these ranges, IgM HLC ratios were abnormal in all WM presentation sera tested, including 15 with non-quantifiable SPE. Despite discordance in quantitation, responses assigned with HLC assays showed excellent agreement to those based on international guidelines using SPE or total IgM; although abnormal HLC ratios indicated residual disease in some patients with negative electrophoresis results. CONCLUSIONS: Nephelometric assessment of IgMκ and IgMλ HLC pairs offers a quantitative alternative to traditional laboratory techniques for the measurement of monoclonal IgM and may aid in the management of WM. Clin Cancer Res; 22(20); 5152-8. ©2016 AACR.

IgA kappa/IgA lambda heavy/light chain assessment in the management of patients with IgA myeloma.

BACKGROUND: Accurate quantification of immunoglobulin A (IgA) monoclonal immunoglobulins by serum protein electrophoresis (SPEP) can be difficult and can impact the assessment of response among patients with multiple myeloma (MM). Therefore, there is a need to identify new assays that better reflect disease burden and response to treatment, and correlate with patient outcome. IgA Hevylite (HLC) measures IgA kappa and IgA lambda separately and provides precise quantitative measurements of the monoclonal IgA expression and polyclonal-isotype matched suppression. In the current study, the authors assessed the usefulness of these assays in the diagnosis of IgA MM and sought to comment on the prognostic value of the assays. METHODS: A study of 157 patients with IgA MM for whom diagnostic samples were available was performed. HLC measurements were performed on a nephelometer and the results were compared with those of electrophoresis. RESULTS: All presentation sera (100 IgA kappa specimens and 57 IgA lambda specimens) were found to have abnormal IgA HLC ratios (IgA kappa median ratio: 336.2 [range, 8.2-7353] and IgA lambda ratio: 0.011 [range, 0.0003-0.45]). In comparison, SPEP bands were quantifiable in only 105 of 157 samples (67%) (median, 28.5 g/L [range, 2.2 g/L-98 g/L]). Of the total of 157 patients, 12 patients (8%) presented with oligosecretory myeloma (<10 g/L; including 4 patients with nonquantifiable SPEP bands). HLC uniquely allows for the measurement of isotype paired suppression, which was found to be associated with shortened overall survival in the current study. CONCLUSIONS: In the current study, IgA HLC ratios were found to be abnormal in all patients and the assay was able to produce quantifiable results in more MM sera than either SPEP or total IgA, potentially representing a solution to the issue of comigration and oligosecretory MM. These preliminary data require confirmation in larger prospective trials to validate the usefulness of IgA HLC.

Impact of initial FDG-PET/CT and serum-free light chain on transformation of conventionally defined solitary plasmacytoma to multiple myeloma.

PURPOSE: Solitary plasmacytoma (SP) is a localized proliferation of monoclonal plasma cells in either bone or soft tissue, without evidence of multiple myeloma (MM), and whose prognosis is marked by a high risk of transformation to MM. EXPERIMENTAL DESIGN: We studied the impact of FDG-PET/CT (2[18F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography) on the risk of transformation of SP to overt MM among other markers in a series of 43 patients diagnosed with SP. RESULTS: Median age was 57.5 years; 48% of patients had an abnormal involved serum-free light chain (sFLC) value, and 64% had an abnormal sFLC ratio at diagnosis. Thirty-three percent had two or more hypermetabolic lesions on initial PET/CT, and 20% had two or more focal lesions on initial MRI. With a median follow-up of 50 months, 14 patients transformed to MM with a median time (TTMM) of 71 months. The risk factors that significantly shortened TTMM at diagnosis were two or more hypermetabolic lesions on PET/CT, abnormal sFLC ratio and involved sFLC, and to a lesser extent at completion of treatment, absence of normalized involved sFLC and PET/CT or MRI. In a multivariate analysis, abnormal initial involved sFLC [OR = 10; 95% confidence interval (CI), 1-87; P = 0.008] and PET/CT (OR = 5; 95% CI, 0-9; P = 0.032) independently shortened TTMM. CONCLUSIONS: An abnormal involved sFLC value and the presence of at least two hypermetabolic lesions on PET/CT at diagnosis of SP were the two predictors of early evolution to myeloma in our series. This data analysis will need confirmation in a larger study, and the study of these two risk factors may lead to a different management of patients with SP in the future. .

Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma.

BACKGROUND: Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex. METHODS: A total of 50 patients with RRMM who were treated with long-term Len for ≥ 2 years from 2 Intergroupe Francophone du Myélome (IFM) centers (Lille and Nancy) were included in the current study. RESULTS: The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for ≥ 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for ≥ 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to <3 years and for ≥ 3 years (P=025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series. CONCLUSIONS: The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex.

[Brentuximab vedotin: new treatment for CD30+ lymphomas]. / Brentuximab vedotin: nouvelle option thérapeutique dans la prise en charge des lymphomes CD30+

Brentuximab vedotin is a new antibody-drug conjugate composed of the anti-CD30 chimeric monoclonal antibody and the potent antimicrotubule drug monomethylauristatin E. In two phase II clinical trials, treatment with single-agent brentuximab vedotin resulted in response rates of 75% in relapsed/refractory Hodgkin lymphoma and 86% in relapsed/refractory systemic anaplastic large-cell lymphoma. Peripheral sensory neuropathy (40%) and neutropenia (20%) were the most frequent side effects, generally mild and manageable. After a large use in a compassionate program, brentuximab vedotin was approved in France in October 2012 for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients non eligible for autologous transplantation, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.