High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement

AbstractThe role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age ≥18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated

Diagnostic challenges of early Lyme disease: Lessons from a community case series

<p>Abstract</p> <p>Background</p> <p>Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown.</p> <p>Methods</p> <p>A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments.</p> <p>Results</p> <p>The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease.</p> <p>Conclusion</p> <p>For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations.</p

Panduan untuk penderita leukemia

xiv, 164 hlm. ; 23 c

Pedoman pasien leukemia

xiv+164hlm.;24c

Diagnostic performance of(18)F-FDG-PET/CT compared to standard skeletal survey for detecting bone destruction in smouldering multiple myeloma: time to move forward

Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false-negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to(18)F-FDG-PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83 center dot 1% (95% confidence interval: 72 center dot 0-90 center dot 5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM

Evaluation of Whole-Body MRI (WB-MRI) in Smoldering Multiple Myeloma (SMM)

Introduction Whole-body magnetic resonance imaging (WB-MRI), including multiplanar multisequence technique with diffusion weighted images, is a novel imaging technique being evaluated for patients with multiple myeloma (MM). WB-MRI is ideal for this population due to its high sensitivity for bone marrow signal changes and full anatomic coverage from vertex to mid-thighs. It is well established that patients with unequivocal focal lesions on MRI have worse outcomes. Currently the IMWG recommends that all patients with smoldering multiple myeloma (SMM) undergo WB-MRI (or whole spine MRI if WB-MRI is not available) to rule out two or more focal lesions which would classify the patient as having symptomatic myeloma requiring treatment. There is a clear benefit of using MRI for the detection of early focal myeloma lesions however less is known about findings in the SMM population. Detection of subtle findings such as one small focal lesion or heterogeneous bone marrow in WB-MRI has unknown clinical significance that needs to be further evaluated. This study aimed to evaluate the sensitivity of WB-MRI compared to other highly sensitive functional imaging modalities in patients with SMM both at baseline and after treatment. Methods Imaging of patients with WB-MRI performed at the National Institutes of Health Clinical Center Myeloma Program were reviewed and compared to whole spine MRI and 18F-FDG PET/CT completed at the same timepoint. The majority of patients were being evaluated for enrollment on clinical trials. Patients had undergone a WB-MRI with a 3-Tesla system either as a baseline study, after completion of induction treatment, or during follow up determined by the time DWI became available at our institution. The imaging protocol included sagittalT1 weighted (W) and Short tau inversion recovery (STIR) for spine and coronal, axial T1W and axial T2 TSE pulse sequences. The functional component included diffusion weighted imaging in the axial plane (b=0 and 900sec/mm2). Radiological interpretation was performed by two readers using myeloma response assessment and diagnosis system (My-RADS) {Messiou, 2019 #340}. WB-MRIs were categorized as positive if focal lesions or diffuse/heterogenous pattern of bone marrow infiltration were present. Similarly, 18F-FDG PET/CTs and whole spine MRIs were classified as positive if focal lesions or diffuse/heterogenous pattern of bone marrow were present. Results A total of 34 patients with SMM and 5 patients with relapsed refractory multiple myeloma (RRMM) had sequential WB-MRI and 18F-FDG PET/CT. Figure 1 summarizes the radiological data of the SMM population. Eleven of these patients had PET/CT, whole spine MRI, and WB-MRI at baseline. Twenty-five patients had PET/CT and WB-MRI completed after at least 8 cycles of treatment. Thirteen patients had consistently negative imaging at baseline, 7 of which also had negative imaging after treatment, while 2 patients were found to have new lesions seen on WB-MRI after treatment. Six patients had resolution of positive imaging seen at baseline after treatment. Among the 17 patients with a positive WB-MRI, 12 (71%; 95% CI 47% - 87%) had a negative correlating PET/CT. Among 5 patients with positive PET/CT at the same time point as a WB-MRI, only 1 (20%; 95% CI 2% - 64%) correlated to a negative WB-MRI. Figure 2 depicts findings from patients with RRMM for comparison. All imaging modalities showed multiple focal findings in all 5 patients. Conclusions This study depicts the high sensitivity of WB-MRI in the SMM population. Such a high sensitivity is especially needed in SMM and early myeloma when disease burden is lower and the decision for treatment is being considered. In comparison to the RRMM population where all three imaging modalities easily detect multiple focal lesions, WB-MRI tends to identify myeloma involvement in the SMM patients more than the other imaging techniques. This suggests the importance of utilizing WB-MRI when diagnosing SMM. In the SMM population, the prognostic significance of lesions that are discrepant between MRI and FDG PET/CT is not yet known. Further follow up is needed to evaluate any difference in hard endpoints such as progression free survival between patients with positive findings described by WB-MRI. Disclosures No relevant conflicts of interest to declare

Assessment of Discordance Among Smoldering Multiple Myeloma Risk Models

This cohort study assesses the concordance of 3 models to stratify risk for progression to multiple myeloma in an independent cohort of patients with smoldering multiple myeloma

Using Current Clinical Markers to Define High Risk Smoldering Multiple Myeloma: Agree to Disagree

Introduction Defining high risk (HR) smoldering multiple myeloma (SMM) is becoming increasingly important as multiple clinical trials are actively investigating the role of early treatment. On average, patients with SMM progress to multiple myeloma (MM) at a rate of 10% per year for the first 5 years (Kyle 2007). Several classification systems have been developed to identify patients with a higher rate of progression, including two commonly used models: the 2008 Mayo Clinic model and the PETHEMA (Programa de Estudio y Tratamiento de las Hemopatias Malignas) model. The 2008 Mayo Clinic model incorporates M-protein (>3 g/dL), bone marrow plasma cell percentage (BMPC%) >10%, and a ratio of involved to uninvolved serum free light chains (sFLCr) >8. Patients with all three characteristics had a 76% risk of progression to MM in 5 years (Dispenzieri 2008). The PETHEMA model uses the proportion of BMPCs with aberrant plasma cell phenotype on flow cytometry (>95%) and reduction in uninvolved immunoglobulins (immunoparesis) to identify HR patients. Patients with both risk factors had a 5-year rate of progression to MM of 72% (Perez-Persona 2007). The 2008 Mayo Clinic model was validated prior to the International Myeloma Working Group reclassification of MM in 2014. Therefore, in 2018, Mayo Clinic proposed a new model to define HR SMM referred to as "2/20/20": M-protein >2 g/dL, BMPC% >20%, and sFLCr >20 (Lakshman 2018). The median time to progression for the HR group (2-3 risk factors) was 29 months, compared to 110 months in the low risk (LR) group (0 risk factors). Previously, a high discordance rate among the 2008 Mayo model and the PETHEMA model was reported (Cherry 2013). In this study, we aim to define the concordance among patients defined as HR SMM by the aforementioned models in an independent sequential patient cohort. Methods The medical records of patients sequentially assigned a diagnosis of SMM by the myeloma program at the NIH Clinical Center between April 2010 to July 2019 were reviewed. Patients with myeloma defining events were excluded (i.e. MM). Each patient was assigned a risk score based on the 2008 Mayo Clinic model, the 2018 Mayo Clinic model, and the PETHEMA model. The distribution of patients in the LR, intermediate (IR), and HR groups were compared between the models. Concordance ratios were calculated between the three models. Results A total of 236 patient records were reviewed and per the 2014 IMWG criteria, 138 patients were identified as having SMM. Two patients did not have bone marrow flow cytometry samples and thus could not be classified by the PETHEMA model. Therefore, 136 patients were stratified by risk based on all three models (Table 1,2). The rate of concordance between the 2008 Mayo Model and the PETHEMA model was 31.6% (95% CI: 24.4-39.8%), similar to previously published results. The concordance between the 2018 Mayo Model and the PETHEMA model was slightly higher at 44.8% (95% CI: 36.7-53.2%; P=0.0337). There was significant discordance between the models in classifying patients as HR versus non-HR (Table 3). However, the 2018 Mayo Clinic model had a higher concordance with the PETHEMA model (27.2%; 95% CI: 20.4-35.3%) than the 2008 Mayo Clinic model (4.4%; 95% CI:1.8-9.5%). Conclusions The accurate identification of SMM patients at highest risk of developing MM remains elusive and no one model has been found to be superior than the other. As this study indicates, a significant number of patients may be classified as "HR" according to the PETHEMA model while simultaneously be defined as "LR" based on the Mayo Clinic models. While the 2018 Mayo Clinic model has a higher concordance rate to the PETHEMA model, it remains significantly discordant. These results indicate that the current clinical variables used to determine risk are not reliable. This is likely due to the fact that they are markers of disease burden rather than biology and risk is subject to increase over time (Landgren 2019). It is time for genomic signatures which signify varying biology to be incorporated into risk models. The treatment of HR SMM is currently being investigated in multiple clinical trials. As the results from these trials are published, the data will need to be scrutinized as to how patients were defined as "HR" in order to compare results. At this time, it remains unclear which patients warrant early intervention and it is imperative that patients with SMM be exclusively treated on clinical trials. Disclosures Mailankody: Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Merck: Other: IDMC; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding

A Phase II Pilot Study of Avelumab in Combination with Hypofractionated Radiotherapy in Patients with Relapsed Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is the 2nd most common hematologic malignancy and remains incurable despite significant treatment advances over the last decade. Patients with relapsed/refractory multiple myeloma (RRMM), who have exhausted available therapies, have limited treatment options and a median survival as brief as 6 months (Richardson PG et al., Oncology 2010). Immune checkpoint inhibitors (CPI) have dramatically changed treatment paradigms in multiple cancers, with growing evidence that radiation therapy (XRT) may synergize with these agents via the abscopal effect. MM cells express high levels of PD-L1. Preclinical models have demonstrated rejection of murine myeloma when PD-L1 blockade was combined with XRT (Kearl TJ et al., Journal of Immunology 2013), as well as longer survival in myeloma-bearing mice compared to controls (Jing W et al., Journal for ImmunoTherapy of Cancer 2015). Early phase single arm clinical trials with combinations of immunomodulatory drugs (IMiDs) and CPI showed response rates between 33 and 76% (Pianko MJ et al., Stem Cell Investigation 2017)(San Miguel J et al., Blood 2015)(Badros A et al., Blood 2017). However, subsequent phase 3 studies revealed a potential safety signal of this combination (FDA 2017). Nonetheless, a subset of patients appear to attain durable responses (Badros A et al., Blood Advances 2019). CPI combined with other therapies such as XRT, that help to prime the immune system, hold great promise in the treatment of patients with RRMM. Herein, we describe our phase II study of avelumab, an anti-PD-L1 IgG1 antibody with potential antibody-dependent cellular cytotoxic properties, in combination with XRT in patients with RRMM. Methods: Trial Design: The primary endpoint of this trial is to assess the systemic response rate with the combination of avelumab and XRT in the treatment of extramedullary plasmacytomas or active lytic lesions in patients with RRMM using the 2016 IMWG response criteria. Secondary endpoints include determination of complete response rate, progression-free survival, and overall survival. Patients will undergo bone marrow biopsies and imaging (PET/CT and DW-MRI) at baseline, during disease response evaluations, and at the end of treatment. Treatment: Treatment consists of a 4-week lead-in with avelumab at a flat dose of 800mg IV every 2 weeks followed by concurrent XRT of 5Gy for 5 consecutive days directed toward the plasmacytoma/lytic lesion (Figure 1). Monotherapy avelumab, 800mg IV every 2 weeks, will continue indefinitely until disease progression or unacceptable toxicity. Analysis: This is a single arm trial with a Simon minimax two-stage phase II trial design that will enroll up to 27 patients. The first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued due to futility. If 1 or more of the first 13 patients have a response, then accrual will continue until a total of 27 evaluable patients have been treated in the second stage. This will provide a two-sided alpha of 5% and a Power of 80% to rule out an ORR of 5% in favor of a response rate of 20%. Response fractions and time to event endpoints will be reported along with 90 and 95% two-sided confidence intervals with nominal p values. Eligibility: Patients must have previously treated relapsed MM or RRMM refractory to, ineligible for, or intolerant of, available myeloma therapies and have ≥ 1 extramedullary plasmacytoma and/or lytic lesion. Lesions must be amenable to, and clinically indicated for, treatment with localized XRT. Eligible patients must have documented evidence of progressive disease on, or after, their most recent regimen as defined by the IMWG criteria. They must have achieved at least a minimal response to one or more prior regimens. Exclusionary criteria include patients with: clinically unstable lesions where a delay in XRT may be detrimental; active autoimmune diseases or history of serious autoimmune-related disorders; uncontrolled intercurrent illnesses; concurrent use of immunosuppressant medications; and recent or current anti-cancer treatment prior to the first dose of avelumab. Current Enrollment: This study is actively enrolling patients to the first stage. At the time of this submission, 4 patients have been enrolled and have received at least one dose of trial therapy. Clinical trial registry number: NCT03910439. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: avelumab not approved in myelom

The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other