Clinical Features and Outcomes of Unifocal Adult Langerhans Cell Histiocytosis

Purpose: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that presents with a wide spectrum of clinical diseases, ranging from single-organ lesions to systemic disease. Although previously thought of as an immune disorder, LCH was reclassified as an inflammatory myeloid neoplasm in the 2016 Histocyte Society classification after discovery of BRAF V600E or MAP2K1 gain-of-function mutations and evidence of clonality in most LCH patients. In this revised classification, LCH was divided into single-system LCH, pulmonary LCH, or multisystem LCH. However, there is a lack of data on clinical features and outcomes in the subgroup of "unifocal" non-pulmonary LCH in adults. In this study, we sought to address the gaps in knowledge for unifocal adult LCH utilizing our institution's experience over 20 years. Methods: We retrospectively reviewed the medical records of 189 adult patients (defined as >18 years old at diagnosis) with histopathologically confirmed LCH who were seen at our tertiary referral center between 1997 and 2018. Of these, 44 met criteria for unifocal LCH at diagnosis after careful exclusion of other sites of disease involvement. Results: We included 44 adult patients with unifocal LCH at diagnosis, with median age 42 years (range 19 to 88) and 55% males. 84% were Caucasians and 50% were smokers. Most commonly involved disease sites included bone (43%), skin (25%), pituitary (14%), and gastrointestinal (11%), with common presenting symptoms of head pain/swelling (25%), skin rash (20%), abdominal pain/diarrhea (11%), and diabetes insipidus (9%). Resection/excision was the most common first line therapy in 24 patients (63%); none had local recurrence and 3 patients developed recurrence at a new site. Radiation was the second most common therapy in 6 patients, with an overall response rate of 83%; none had local recurrence and 1 patient had recurrence at a new site. Other less common first-line treatments included resection followed by radiation (2), topical immunosuppression (2), dexamethasone (1), cladribine (1), smoking cessation (1), and observation (1) (Table 1). Cladribine used as first-line therapy for pituitary LCH resulted in progressive disease, but cladribine used as second-line therapy in 2 cases (including one who had progressed to multisystem disease) resulted in partial remission with no further recurrence in both cases. Patients were followed for a median of 3.8 years (range 0.1 to 18.8), with 5 patients lost to follow-up. By time of last follow-up, 11 (28%) had developed recurrence: 1 had local recurrence, 5 developed disease at a new site within the same system (skin or bone), and 5 developed multisystem disease (Figure 1). Median time to recurrence was 2 years (range 0.2 to 6.6). 2 out of 5 patients tested for BRAF had a V600E mutation, both of whom had isolated unifocal bone disease and remained in complete remission following resection at time of last follow-up. Median overall survival (OS) from time of diagnosis was not reached and overall 5-year OS was 94%. 3 patients died, only 1 of progressive LCH. Conclusion: In our study, most patients with unifocal adult LCH achieved a complete remission with surgical resection or local radiation. None of the patients treated with resection or radiation developed local recurrence, but around 1 in 5 developed distant recurrence within 5 years. However, the overall prognosis was very good, and none of the patients in the cohort progressed to "high-risk" organ (liver, spleen, or bone marrow) involvement or pulmonary involvement. Further studies are warranted to assess the role of MAPK-ERK mutations in the prognosis of unifocal LCH. Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding. Vassallo:Sun Pharmaceuticals: Research Funding; Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.

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Patient Profile and Treatment Patterns in a Commercially Insured Population with Follicular Lymphoma

Blood ◽

10.1182/blood-2019-127237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5880-5880

Author(s):

Nathan H Fowler ◽

Yanni Hao ◽

Stephen Lim ◽

Guifang Chen ◽

Frank Li ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Third Line ◽

Line Of Therapy

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. Patient characteristics and burden of FL are incomplete and vary from previous studies. This study evaluated patient profile, including patient characteristics, treatment patterns, and duration using real-world data. Methods: Using the Truven MarketScan® databases, patients with FL who were newly initiated with FL indicated regimens were identified from 1/1/2010-12/31/2013 (initial treatment identification period). Patients were selected if they were ≥18 years old, had 1 FL ICD-9 code (202.0) as primary or secondary diagnosis, at least 1 FL commonly prescribed systemic anti-cancer therapy after the diagnosis, and did not use any FL indicated regimen in the past 6 months prior to first agent included in the initial treatment identification period. These patents were followed ≥3 months or to June 30, 2018. Primary outcomes were the distribution of regimens by line, the number of patients who switched from first- to second-line therapies, and from second- to third-line therapies. The treatment duration by line of therapy and regimen were also analyzed. Discontinuation was defined as 3 months without receiving a regimen after treatment. Results: This study identified 4,970 patients who initiated treatment for FL. Of these patients, 48.1% were female (n=2,390), with a mean age of 62.0 (SD: 14.0) years. The average follow-up time was approximately 2 years (median: 733 days). In this analysis, 4,970 patients with FL received first-line therapy for 153 days (median: 94 days), 1,985 received second-line therapy (39.9% of patients who received first-line therapy) for 208 days (median: 80 days), and 664 received third-line therapy (13.4% of patients who received first-line therapy) for 117 days (median: 43 days). Of the 4,970 patients on first-line therapy, 453 (9.1%) remained on first-line therapy, 2,532 (51.0%) discontinued treatment, and 1,985 (39.9%) patients switched to the next line of therapy during the follow-up period. Of the 1,985 patients who switched to second-line therapy, 328 (16.5%) remained by the end of follow-up period, 993 (50.0%) discontinued, and 664 (33.4%) switched to the next line of therapy during the follow-up period. Of the 664 patients who switched to third-line therapy, 125 (18.8%) remained, 269 (40.5%) discontinued, and 270 (40.7%) switched to the next line of therapy. The most common first-line regimens in descending order received by patients were rituximab (n=1,478, 29.7%), R-CHOP (n=1,368, 27.5%), BR (n=1,050, 21.1%), R-CVP (n=371, 7.5%), and FCR (n=63, 1.3%). Second-line treatment regimens were (N=1,985) rituximab (n=992, 50.0%), BR (n=202, 10.2%), R-CHOP (n=138, 7.0%), and R-CVP (n=120, 6.1%). Third-line treatment regimens were (N=664) rituximab (n=228, 34.3%), BR (n=91, 13.7%), R-CHOP (n=75, 11.3%), cyclophosphamide (n=35, 5.3%) and R-CVP (n=31, 4.7%). Conclusion: This data set describes the percentage of patients that transition from first- to second-line and second- to third-line treatment for FL. The primary regimens used across the treatment lines conform to those recommended by the NCCN guidelines. In addition, smaller numbers of non-recommended regimens were reported. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lim:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Consultancy, Employment. Li:Novartis Pharmaceuticals Corporation: Employment. Arcona:Novartis Pharmaceuticals Corporation: Employment.

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Recombinant Interferon-α Reduces Thrombotic Events in Patients with Polycythemia Vera

Blood ◽

10.1182/blood-2019-131605 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1664-1664

Author(s):

Spencer Krichevsky ◽

Ghaith Abu Zeinah ◽

Claudia Sosner ◽

Diana Jaber ◽

Niamh Savage ◽

...

Keyword(s):

Research Funding ◽

Advisory Board ◽

Interferon Α ◽

First Year ◽

First Line ◽

Thrombotic Risk ◽

Vein Thrombosis ◽

First Line Therapy ◽

Line Therapy ◽

Thrombotic Complications

Introduction: Polycythemia vera (PV) is characterized by an increased red cell mass resulting in whole blood hyperviscosity, a strong predictor for thrombosis which remains a significant cause of morbidity and mortality1. Leukocytosis, thrombocytosis, and phlebotomy (PHL) rates are reported additive risk factors for thrombosis but their relative significance has been debated. PHL and cytoreductive therapy mitigates the risk of thrombotic complications. However, the relevance of these parameters remain insufficiently studied2,3. Our primary objectives were to assess the significance of these risks and their associations with thrombosis. We also evaluated whether first-line interferon-α (rIFNα), hydroxyurea (HU), and phlebotomy-only (PHL-O) therapy is associated with reduced thrombotic risk. Methods: After IRB approval, 328 patients (pts) were evaluated after diagnosis according to PVSG criteria (1974-2007), published Weill Cornell criteria (2008-2016)4, or WHO 2016 criteria. Demographics, clinical history, laboratory values, bone marrow findings, and genetic mutations were collected by querying our platform containing aggregated clinical data, the Observational Medical Outcomes Partnership Common Data Model5. Using intention-to-treat analysis, pts were assigned to a first-line therapy defined as continuous cytoreductive therapy for ≥1 consecutive year or PHL-O. Covariate differences between the first-line therapy groups at diagnosis were determined using χ2 tests for categorical variables. Overall survival (OS) was derived by the Kaplan-Meier estimator and comparisons of thrombosis risk were performed using a Cox proportional hazards model adjusted for clinically significant covariates such as age. Results: The characteristics of 165 men (50.3%) and 163 women (49.7%) with PV are shown in Table 1. Followup extended up to 45.0 years (yrs) with a median of 10.3 yrs. Median OS was 32.5 yrs. Splanchnic vein thrombosis, stroke, and deep vein thrombosis were the most common events. Median age at first event was 59.1 yrs. Predisposing factors associated with thrombosis included uncontrolled HCT, increasing leukocytosis, and ≥5 PHL during the first year after diagnosis. Elevated HCT was the greatest contributor to thrombosis: males with HCT of 53.0% had thrombotic complications at 10 times the rate of those with HCT of 43.5% and females with HCT of 51.9% had a thrombosis at 6 times the rate of those with HCT 40.0% (Fig 1). Pts with leukocytosis (30.8x109/L) had a thrombosis at 2.5 times the rate of those with a white blood cell (WBC) value of 9.4x109/L. There was a weak association between platelet (PLT) count and thrombosis (data not shown). The mean number of first-year PHL was 5.3±4.3; those pts requiring ≥5 had a thrombosis at 2 times the rate of those that required less (p=0.011). The difference in cumulative incidence of thrombotic events within 10 yrs was statistically significant for pts requiring ≥5 first-year PHL (p=0.031, Fig 2). There was a significant difference in the cumulative incidence of thrombosis during the first 10 yrs of diagnosis dependent on first-line therapy (PHL-O: n=117, HU: n=84, rIFNα: n=40) (p=0.021, Fig 3). The apparent superiority of IFN over HU and PHL in this retrospective study is suggested by 10 year cumulative incidences of thrombotic events of 3.2, 18.0, and 30.6%, respectively. Discussion: There was a significant correlation between HCT, WBC count, and PHL requirements, but not PLT count, with thrombotic events. Elevated HCT was the most important risk factor. However, leukocytosis and first-year PHL rates also contribute as indicated by the higher hazard ratios. This suggests a need for cytoreductive therapy from disease onset. Our analysis shows that rIFNα reduces thrombotic risk when compared to HU and PHL. Conclusion: Multivariate analysis indicates that elevated HCT level is the most important parameter for correlation with thrombosis within the first 10 yrs of illness. However, WBC and PHL rates are also significant. Since thrombosis occurs from the time of diagnosis, our data suggest the need for cytoreductive intervention from onset. Analysis of the three most common first-year therapies shows that HU and PHL are inferior to rIFNα in reducing thrombotic risk. Disclosures Ritchie: Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Genentech: Other: Advisory board; agios: Other: Advisory board; Tolero: Other: Advisory board; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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In Multiple Myeloma Progression Free and Overall Survival in the Relapsed Setting Remains Poor with Early Exposure to Novel Agents: Experience from a Real-World Cohort

Blood ◽

10.1182/blood.v126.23.4261.4261 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4261-4261 ◽

Cited By ~ 1

Author(s):

Christopher P. Venner ◽

Nizar J Bahlis ◽

Paola Neri ◽

Irwindeep Sandhu ◽

Peter Duggan ◽

...

Keyword(s):

Research Funding ◽

Response Rate ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Third Line Therapy ◽

First Relapse ◽

Third Line ◽

Line Of Therapy

Abstract Introduction: With the widespread adoption of novel agents (NA) in all lines of therapy patients are being exposed to both proteosome inhibitors (PIs) and immunomodulatory drugs (IMiDs) early in their treatment course. This has lead to marked improvements in survival in the frontline setting. Data is limited with respect to patient outcomes after exposure to both these drug classes in the real world setting. Here we present our experience examining outcomes after each line of therapy whereby bortezomib-based induction followed by lenalidomide-based therapy at first relapse has become the standard of care. We further explored the outcomes of patients who were exposed to both active classes of drugs within their first 2 lines of therapy. Patients and methods: This series includes patients seen through the provincial Alberta Myeloma and Dysproteinemia Program in Canada. Only patients treated between 2005-2013 were included to allow at least 2 years of follow-up beyond first line therapy. Only those treated with a NA-containing regimen as part of their first line treatment were examined. The cohort was split based on eligibility for autologous stem cell transplant (ASCT). Double exposed patients were those who had been treated with, but were not necessarily refractory to both an IMiD and PI within the first 2 lines of treatment. Outcomes were measured after first, second and third line therapy. Survival outcomes were measured in months (m). OS was measured from the start of each line of therapy until death or last follow-up. PFS was from the start of each line of therapy to relapse, death or last follow-up. Response was measured as per the most recent International Myeloma Working Group criteria. Near complete response (nCR) was used when the monoclonal protein disappeared on protein electrophoresis but was not confirmed by immunofixation. Results: Two hundred forty eight patients had received upfront therapy (non-ASCT = 113 and ASCT = 135). One hundred twenty seven had received second line therapy (non-ASCT = 62 and ASCT = 65). Sixty-four had received third line therapy (non-ASCT = 31 and ASCT = 33). The median OS and PFS after each line of therapy are shown in table 1. After first line therapy the OS (p < 0.001) and PFS (p< 0.001) were significantly better in the ASCT cohort. There were no significant differences in survival outcomes based on transplant eligibility in subsequent lines of therapy (figure 1A and B). The overall response rate to third line therapy was 45% (VGPR = 14% and nCR = 7%) for non-ASCT patients and 52% (VGPR = 15% and nCR = 6%) for ASCT patients. Fifty-five percent of non-ASCT patients failed to respond during third line therapy (34% with progressive (PD) and 21% with stable disease (SD)). Forty-eight percent of ASCT patients failed to respond (PD = 27% and SD = 21%). Forty-seven patients were double exposed within the first 2 lines of therapy (non-ASCT = 26 and ASCT = 21). In this cohort, the OS and PFS after double exposure (i.e. third line therapy) was 15m and 5m respectively with no significant difference based transplant eligibility (figure 1C and D). The response rate to third line therapy was 46% (VGPR = 17% and nCR = 8%) for ASCT patients and 43% (VGPR = 14% and nCR = 5%) for non-ASCT patients. Fifty-five percent failed to respond (PD = 38% and SD = 17%) in the non-ASCT group. Fifty-seven percent failed to respond (PD = 38% and SD = 19%) in the ASCT group. Summary: The introduction of NAs earlier in the management of patients with myeloma has improved OS. This is driven by improvements in PFS to frontline therapy and after first relapse. However, with current therapeutic approaches patients will be exposed to both IMiDs and PIs much earlier in their disease. In many jurisdictions, the limited treatment options in third line and beyond, especially in double exposed patients, poses a significant therapeutic challenge. Durable responses are limited in this setting with most patients relapsing after only 6 months. In addition, approximately a third of patients have overtly progressive disease. Interestingly, front-line ASCT eligibility had no impact on outcome with subsequent relapses, emphasizing the fact that ASCT only improves the outcome for the line in which it is employed. Further study regarding resistant mechanism and clonal evolution after exposure to both IMiDs and PIs will be important in developing rationally designed therapeutic regimens for this population. Disclosures Venner: J&J: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Some patients in this series will have received frontline lenalidomide which is not yet an approved indication for this drug in Canada.. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Research Funding. Neri:Celgene: Research Funding. Sandhu:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Belch:Janssen-Cilag: Consultancy. Jimenez-Zepeda:Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria.

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Langerhans Cell Histiocytosis: A Single Institution Retrospective Analysis of Eleven Patients

Blood ◽

10.1182/blood.v124.21.5458.5458 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5458-5458

Author(s):

Vittorio Stefoni ◽

Alessandro Broccoli ◽

Beatrice Casadei ◽

Enrico Derenzini ◽

Letizia Gandolfi ◽

...

Keyword(s):

Radiation Therapy ◽

Retrospective Analysis ◽

Steroid Therapy ◽

Langerhans Cell Histiocytosis ◽

Langerhans Cell ◽

Unknown Etiology ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Abstract Langerhans cell histiocytosis (LCH), is a rare disorder which has a substantially unknown etiology, pathophysiology, and may manifest through a variety of clinical presentations ranging from solitary eosinophilic granuloma to severe multisystem disease. LCH is more common in children, although it can affect any age; the most common sites of involvement are bone, skin, and lung. From a histological point of view LCH derives from accumulation of proliferating cells with surface markers and ultrastructural features similar to cutaneous Langerhans cells, intermixed with inflammatory cells, particularly eosinophils. Below, a retrospective analysis of LCH patients treated at our institution. Between 1997 and 2013 we have treated 11 LCH patients, including 6 females and 5 males with a median age at time of diagnosis of 42.9 years (range 22.2-62.3). All diagnoses were reviewed by our pathologist. With regard to the site at onset, 9 patients had bone involvment, among these, four patients had only bone involvment, the other five patients also lung, oral cavity and lymph nodes. At time of onset 4 patients showed no symptoms, while the remaining 7 showed a variety of symptoms ranging from B symptoms to tinnitus, dizziness, and other neurological symptoms such as diplopia. Among the study group 6 patients had multisystemic involvement. All patients except one had CT scan performed before, during, and at follow-up, the remaining patient was studied and followed through follow-up with PET scan. As first-line therapy 8 patients underwent chemotherapy, 2 patients radiation therapy, 1 patient required only steroid therapy. The most frequently used chemotherapy regimen for these 8 patients was MACOP-B, a third generation, CHOP-like regimen. Responses to first-line therapy were as follows: 7 complete remissions (CR), resulting with chemotherapy (5), radiation therapy and steroid therapy, two partial remissions (both obtained with chemotherapy) and two stable diseases (1 with chemotherapy and 1 with radiation therapy). Two patients relapsed, of whom one has ran several lines of chemotherapy, including autologous stem cell transplantation. Both are alive at the time of the last follow-up. To date all patients are alive but one, who died of pulmonary embolism while he was in stable disease. Six patients are in CR (60%), two in SD (20%) and two in PD (20%). In conclusion, our monocentric experience of 11 LCH patients confirms what reported in the literature in terms of heterogeneity of presentation, age, sites of involvement, symptomatology and treatment demanded. Coming to the the results our retrospective analisys shows that ten of the eleven study population patients (90.9%) are to date still alive after a significant median time of follow-up; six out of these ten patients (60%) are in CR. Disclosures No relevant conflicts of interest to declare.

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A Recent Update of Three Consecutive Prospective Trials with High-Dose Therapy and Autograft, without or with Rituximab, as Primary Treatment for Advanced-Stage Follicular Lymphoma (FL) Shows a Sizeable Group of Patients Surviving in Continuous Complete Remission up to 16 Years After the End of Treatment: Should We Still Consider FL An Incurable Disease ?.

Blood ◽

10.1182/blood.v114.22.882.882 ◽

2009 ◽

Vol 114 (22) ◽

pp. 882-882 ◽

Cited By ~ 1

Author(s):

Corrado Tarella ◽

Marco Ladetto ◽

Fabio Benedetti ◽

Umberto Vitolo ◽

Alessandro Pulsoni ◽

...

Keyword(s):

Complete Remission ◽

Disease Progression ◽

Financial Support ◽

High Dose ◽

Advanced Stage ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Abstract Abstract 882 Background. Three consecutive trials have been performed in Italy over the last 18 years, to verify the efficacy of the use of High-Dose Sequential Chemotherapy (HDS) and autograft as first-line therapy for high-risk Follicular Lymphoma (FL) <60 yrs. We present the last update with 10 yrs. of median follow-up. Patients and Methods. The HDS regimen has been previously described (Corradini P et al, Blood 1997; Tarella C et al, Stem Cells 1998). Briefly, it consists of intensive debulking (2 APO courses +/− 2 DHAP courses) followed by the high-dose phase, including the sequential administration of etoposide (2 g/sqm), methotrexate (MTX) (8 g/sqm) and cyclophosphamide (CY) (7 g/sqm). PBPC collection is scheduled after the last course to maximize the “in vivo purging effect” operated by high-dose chemotherapy. The final autologous stem cell transplant (auto-SCT) conclude the program, two conditioning regimen have been employed, either the BEAM schedule or the Mitoxantrone/L-PAM combination. In the most recent schedule, Rituximab was included in place of MTX. In details, 2 Rituximab doses were administered before CY, after CY and after auto-SCT, with the aim of further improving disease control and the in-vivo purging. The first trial was a single Center phase II study exploring both feasibility and efficacy of the HDS program as first line therapy in advanced-stage indolent lymphoma (1991-1998, 26 FL patients) (Tarella C et al, Leukemia 2000); a subsequent multicenter phase 2 trial was then started at national level (GITMO, Gruppo Italiano Trapianto Midollo Osseo), to verify the efficacy of HDS in advanced-stage FL in a multicenter setting (1996-1999, 92 patients) (Ladetto M et al, Blood 2002); lastly, a muticenter phase 3 study was performed together with GITMO and IIL (Intergruppo Italiano Linfomi) Centers, comparing Rituximab supplemented HDS (R-HDS) vs. CHOP-R in aaIPI 2-3 FL (2000-2005, 68 patients in the R-HDS arm) (Ladetto M et al, Blood 2008). Overall, 186 patients have been treated with HDS, updated results have been obtained for 168 of them. They all had a diagnosis of FL (grade 1-2: 71%) and always presented with advanced stage, their median age was 48 yrs., LDH was high in 48%, BM involved in 77%. Results. 140 patients out of 168 (83%) attained Complete Remission (CR); there were 6 early toxic deaths (3.6%); 8 patients had Partial Remission (4.8%) and 14 had no response (8.3%), soon followed by disease progression. So far 14 patients (8.3%) developed secondary myelodysplasia or acute leukemia (sMDS/AL), and 7 patients (4.2%) had a secondary solid neoplasia. As of July 2008, 50 of 168 patients died, due to: i. early toxicity (6 patients); ii. disease progression (25 patients, 15%); iii. second neoplasia (12 patients, 7.1%); iv. other causes (7 patients, 4.2%). Thus, at a median follow-up of 10 yrs., 118 patients (70.2%) are alive, and 80 (48%) are in their 1st continuous CR (CCR), and most of them are also in molecular remission. The actuarial OS and DFS curves are reported in Figures 1A and B. The latest relapse has been recorded at 8 yrs since HDS. So far, 50 patients (30%) are presently in their 1st CCR between 8 and 16 yrs after HDS. Conclusions. i. advanced stage FL treated upfront with the intensive HDS regimen had a prolonged survival, with median survival not yet reached after 10 yrs. of follow-up; ii. main causes of death were disease progression and both early and late toxic side effects; iii. approximately half of the patients are long-term survivors without any sign of disease recurrence. This suggest that a prolonged PFS and possibly the disease eradication should be pursued also in advanced-stage FL. Future studies will verify whether these therapeutic goals may be achieved with chemo-immunotherapeutic schemes at least as effective but less toxic and laborious than HDS program with autograft. Disclosures: Tarella: Roche: Honoraria, research financial support. Ladetto:Roche: research financial support. Vitolo:Roche: Lecture fees. Rambaldi:Roche: Honoraria. Corradini:Roche: Honoraria.

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Treatment Patterns and Outcomes Following Initial Relapse in Patients with Relapsed Systemic Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood.v128.22.3338.3338 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3338-3338

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

Morie A. Gertz ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Al Amyloidosis ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a plasma cell disorder characterized by deposition of misfolded insoluble protein fibrils (composed of monoclonal κ or λ light chains) in tissues causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT), when eligible, are standard treatment options but relapses remain inevitable for most patients. However, there is a paucity of literature describing relapsed or refractory patients. We performed a retrospective study to analyze the outcomes upon relapse and the impact of type of therapy and retreatment with the same therapy at relapse. Methods Clinical and laboratory data of 1327 consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Of these patients, 219 (16.5%) were lost to follow-up. Among the remaining 1108 patients, 366 patients experienced a documented hematological or organ relapse or progression requiring change of first line or start of second line therapy and form the current study population. Overall survival (OS) was calculated from start of second line treatment or progression mandating therapy until death from any cause or the date of last follow up. The OS was estimated using the Kaplan-Meier method and log rank test was used to estimate the difference in survival curves. Results The median age was 62.8 years (36.1 - 85.3); 63.1% were males; 64.7% / 59.3% / 11.4% had cardiac / renal / hepatic involvement and 24.2% / 32.1% / 23.3% / 20.3% had MS I/II/III/IV. The median estimated follow up for this cohort was 69.4 months (95% CI; 64.4, 76.8) from the start of first line therapy and 45.2 months (95% CI; 36.5, 50.6) from the start of second line therapy or progression requiring treatment. The median time to second line treatment or relapse /progression mandating therapy was 16.2 months (1-93) from the start of first line therapy. At relapse, 14 patients underwent ASCT, 165 were treated with proteasome inhibitor (PI) based therapy, 83 with immunomodulator (IMiD) based therapy, 33 with alkylator based therapy, 15 with a combination of PI and IMiD, 10 with steroids, 8 with other therapies and 38 did not receive treatment. Among the 366 patients, 124 (33.9%) required change or reinstitution of therapy during follow up at the time of analysis. The median time to third line treatment or relapse /progression mandating therapy was 31 months (95% CI; 24, 40.5) from the start of second line treatment. The median overall survival (OS) was 76.4 months (95% CI; 65.2, 83.6) from the start of first line therapy and 38.8 months (95% CI; 29.6, 52.6) from the start of second line therapy. The type of therapy at relapse (ASCT vs PI vs IMiD vs melphalan vs steroids and others) did not alter the time to next therapy (ASCT, 43.1m; PI, 31m; IMiD, 37m; melphalan, 20.8m; steroids and others, 20m; p=0.3) and OS (ASCT, 66.9m; PI, 51.1m; IMiD, 51.3m; melphalan, 37.2m; steroids and others, 80.7m; p=0.9) from the start of the second line treatment; as depicted in Figure 1. Retreatment with a different drug class (as the first line treatment) at relapse significantly reduced the time to next treatment (32.3m vs 22 m; p= 0.01) as compared to same therapy; but did not have any impact on survival (30.8m vs 51.1m; p = 0.5); as presented in Figure 2. Conclusion This study provides novel information about outcomes of patients with systemic AL amyloidosis who relapse or progress after first line therapy which could be useful in planning salvage therapies and designing clinical trials. Retreatment with a different therapy at relapse improves time to next therapy but does not impact OS. Hence, we conclude that the patients can fare well post relapse/ progression and can benefit from various treatment regimens including retreatment with the same agent. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding.

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Outcomes Are Similar Following Allogeneic Hematopoietic Stem Cell Transplant for Newly Diagnosed Patients Who Received Venetoclax + Azacitidine Versus Intensive Chemotherapy

Blood ◽

10.1182/blood-2021-154392 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3957-3957

Author(s):

Amanda C. Winters ◽

Grace Bosma ◽

Diana Abbott ◽

Mohd Minhajuddin ◽

Craig T Jordan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Advisory Board ◽

Cell Transplant ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

First Remission

Abstract Background: Venetoclax-based therapy regimens are now FDA-approved for treatment of acute myeloid leukemia (AML) in older patients or those unfit to tolerate intensive chemotherapy (IC). Remission rates are high at 60-70% but relapses do frequently occur. Outcomes for newly-diagnosed patients who receive venetoclax-based therapies and proceed to a potentially curative allogeneic stem cell transplant (SCT) have largely been unreported. In the current study we compare outcomes of patients who received SCT following either IC or venetoclax + azacitidine (ven/aza) at the University of Colorado Hospital. Methods: Patients 18 years or older who received SCT in first remission of AML between 2010-2020 were included in the analysis. Patients were stratified into the IC arm if they initially received a backbone of cytarabine and an anthracycline; some patients in this cohort received IC in combination with other targeted agents. Patients who received ven/aza as first-line therapy followed by SCT were grouped in a separate cohort. Demographic and clinical information - including flow cytometry-based (MCF) MRD - was extracted from the electronic medical record. Comparisons of demographic and clinical variables between IC and ven/aza groups were made with t-test, Chi-squared, or Fisher's exact test depending on the nature of the variable. Relapse-free (RFS) and overall (OS) survival were calculated from the day of SCT to the respective endpoint or last documented follow-up using log-rank statistics. Finally, a Cox proportional hazards model was used to assess the interplay between variables pre- and post-SCT. P-values <0.05 were considered significant. Results: We identified 179 patients who received SCT for AML in first remission. Of these patients, 151 received IC and 28 received ven/aza prior to SCT. Patients in the ven/aza group had higher median age than those in the IC group, as well as a higher proportion with adverse ELN genetic risk scoring. Patients in the ven/aza group received less intensive conditioning regimens. Sex, rates of MCF MRD negativity pre-BMT, incidence of severe acute or chronic GVHD, and causes of death were not significantly different between the two groups. There was no difference between the two groups in post-transplant RFS or OS (Figure 1). In a multivariate Cox model of pre-transplant variables predicting OS, the only factor that achieved significance was pre-SCT MCF MRD; the induction regimen was not a multivariate factor. Negative MCF MRD going into SCT was associated with decreased likelihood of relapse, GVHD, and death, respectively. Conclusions: In our cohort of AML patients receiving SCT, we found that ven/aza as a pre-transplant therapy yielded equivalent post-transplant outcomes compared to IC, in a population of older age and with higher ELN genetic risk. MCF MRD pre-SCT was confirmed as a key prognostic factor for post-SCT outcome. These findings support ongoing use of ven/aza as a first line therapy for elderly patients with AML as well as its exploration as a candidate therapy for younger patients. Figure 1 Figure 1. Disclosures Pollyea: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Aprea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kiadis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Agios: Other, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, Servier: Other; Pfizer: Research Funding; Syros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: advisory board; Foghorn: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: advisory board; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board.

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Oral Fludarabine and Intravenous Rituximab (FR) for Chronic Lymphocytic Leukemia (CLL): Long Term Outcomes and Secondary Malignancies in 673 Patients Treated in British Columbia (BC)

Blood ◽

10.1182/blood-2019-125189 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4300-4300

Author(s):

Elysha Vanderveer ◽

Steven J.T. Huang ◽

Helene Bruyere ◽

Tanya Gillan ◽

Charles H. Li ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Secondary Malignancies ◽

Long Term Outcomes ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

The Impact

Background: Oral fludarabine and intravenous rituximab (FR) was the standard first-line therapy for CLL or small lymphocytic lymphoma (SLL) patients (pts) in BC from 2003-2015. Ibrutinib for relapsed/refractory (R/R) CLL was introduced and publicly funded in 2015. Our aim was to review long term outcomes of all CLL/SLL pts treated with FR in BC, including the impact of 2nd line therapy with ibrutinib versus chemoimmunotherapy and to report the risk of secondary malignancies in this population based cohort. Methods: The BC Provincial CLL Database was used to identify all CLL/SLL pts who received first-line FR from 2003-2017. The BC Cancer Registry was used to identify secondary malignancies occurring after FR. Primary outcomes were overall survival (OS) and treatment free survival (TFS), defined as start of FR to next-line therapy or death/last follow-up. Variables examined for impact on OS/TFS included age at FR, gender, primary diagnosis (CLL vs SLL), B symptoms, advanced stage (Rai stage 3-4 CLL, Ann Arbor 1-2 SLL), baseline hemoglobin, lymphocyte count, platelets, LDH and FISH abnormalities. All variables significant on univariate analyses (P<.1) were included in multivariate Cox proportional hazard regression models to identify significant predictors of OS/TFS. Results: 673 pts were identified as receiving FR as first-line therapy for CLL (86%) or SLL (14%). Median time from CLL/SLL diagnosis to FR was 2.5 years (y) (range 0.1-27.3). Median age at FR was 67 y (range 26-91) with 73% ≥ 60 y and 39% ≥ 70 y. Most pts were male (66.1%), had early stage disease (84.2%) with no B symptoms (89.7%) and normal LDH (81.1%). Of 411 pts with pre-treatment FISH testing, prevalence of FISH abnormalities were: 48.5% del13q, 25.7% trisomy 12, 12.9% del11q, 8.0% del17p. Median number of FR cycles was 6 (range 1-10). Median follow-up of living pts from FR was 6.4 y (range 0.2-12.7). 2 y and 5 y OS were 89.4% (95% CI: 86.8-91.6) and 73% (95% CI: 69.0-76.6) respectively; median OS 11.6 y (95% CI: 4.6-13.7 y). 2 y and 5 y TFS were 72% (95% CI: 68-75%) and 37% (95% CI: 33 - 41) respectively, median TFS 3.8 y (95% CI: 1.78-7.09). Those with del17p had significantly worse OS and TFS compared to those without (median OS 5.7 vs 13.7 y, P<.001; median TFS 1.4 vs 3.9 y, P<.001), Fig. 1. Multivariate analysis identified only del17p (HR 4.35, 95%CI: 2.10-9.01, P<.001) and age at FR (HR 1.04, 95% CI: 1.01-1.07, P=.007) as significant predictors of OS, and del17p (HR 4.3, 95% CI: 2.5-7.5, P<.001) as a significant predictor of TFS. During the follow up period, 351 pts (52%) went on to 2nd-line therapy: ibrutinib 87 (including 2 with BR and 1+R), cyclophosphamide-based (CVP/CHOP) +/- R 102, repeat FR 71, FCR 6, F alone 21, bendamustine +/-R 13, chlorambucil+/-R 38, steroids 3, R alone 3, alemtuzumab 2, other chemotherapy 3 and allotransplant 2. Median follow-up after 2nd-line therapy was 2.8 y (range 0.1-10.8). Median OS and TFS from 2nd-line treatment (TFS2) for ibrutinib (n=87) vs. for other treatments (n=264) was: OS not reached vs 5.3 y, P<.001; TFS2 not reached vs 1.2 y, P<.001. These significant differences persisted when analyses were restricted to those who received ibrutinib vs. chemoimmunotherapy (n=169): median OS not reached vs. 6.3 y (P=.002); median TFS not reached vs. 1.7 y (P<.001), Fig. 2. 2 y OS and TFS2 after ibrutinib were 91% (95% CI: 80-96%) and 78% (95% CI: 65-87%), respectively. A total of 202 malignancies were recorded after initiation of FR in 166 pts (24.7%), Table 1. The median time from FR to 2nd malignancy was 2.3 y (range 0.1-13.5). Richter's transformation (RT) occurred in 36 pts (5.3%) at median 1.9 y (range 0.1-13.2) from FR. Most frequent 2nd malignancies were: non-melanoma skin cancer (11.7%), lung (2.5%), colon (2.1%), other heme (1.9%), and prostate (1.8%). There were 4 cases of acute myeloid leukemia (AML), 2 of which received alkylator therapy after FR prior to AML diagnosis. Conclusions: In this large, homogeneous cohort of CLL/SLL pts treated with first-line FR, including nearly 40% of pts ≥ age 70, we demonstrate a short median TFS of 3.8 y; however, a long OS of 11.6 y. Rates of 2nd malignancies are low after this non-alkylator based chemoimmunotherapy regimen. Ibrutinib for R/R CLL/SLL after FR resulted in significantly improved survival over alternate therapy, with excellent 2 yr OS 91% and TFS 78%. These data demonstrate the efficacy of FR and the benefit of ibrutinib over chemoimmunotherapy as second-line therapy for CLL/SLL in the real-world. Disclosures Bruyere: Jenssen: Other: Travel Grant; Celgene: Honoraria. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:Takeda Pharmaceuticals: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Sehn:TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria.

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Superiority of Double over Single Autologous Stem Cell Transplantation as First-Line Therapy for Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.536.536 ◽

2004 ◽

Vol 104 (11) ◽

pp. 536-536 ◽

Cited By ~ 10

Author(s):

Michele Cavo ◽

Claudia Cellini ◽

Elena Zamagni ◽

Patrizia Tosi ◽

Delia Cangini ◽

...

Keyword(s):

Multiple Myeloma ◽

Complete Remission ◽

Autologous Transplantation ◽

High Dose ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Significant Difference ◽

The Impact

Abstract The “Bologna 96” clinical trial was designed in an attempt to prospectively compare a single autologous transplantation (Tx-1) versus double autologous transplantation (Tx-2) as part of first-line therapy for patients with symptomatic multiple myeloma (MM) and less than 60 years of age. Tx-1 was given to support melphalan 200 mg/m2 (MEL-200); Tx-2 was given to support a first course of MEL-200 followed, within 3 to 6 months, by melphalan 120 mg/m2 + busulfan 12 mg/kg. In both arms of the study, autologous transplantation was preceded by 4 courses of VAD and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide 7 g/m2. An analysis was performed using an intent-to-treat approach on 228 patients who were randomly assigned to Tx-1 (n=115 patients, median follow-up of living patients: 45 months) or Tx-2 (n=113 patients, median follow-up of living patients: 54 months). In comparison with Tx-1, Tx-2 prolonged event-free survival (EFS) of 12 months (P=0.001) and time to progression (TTP) of 17 months (P=0.0001). Six-year projected probability of survival (OS) was 44% for Tx-1 and 63% for Tx-2 (P=0.3). The probability of attaining stringently defined complete remission (CR) or near complete remission (nCR) was 35% for Tx-1 and 48% for Tx-2; the sample size analyzed was not powered to detect a statistically significant difference between the two groups. Among patients randomized to Tx-1, attainment of CR or nCR was an essential prerequisite for extended OS (P=0.0001), EFS (P=0.000002) and TTP (P=0.000007). At the opposite, the benefits of double autologous transplantation were the greatest among patients who failed at least nCR. In particular, patients who did not attain CR or nCR after the first autologous transplantation and by study randomization received a second transplantation had a significantly longer duration of OS (P=0.01), EFS (P=0.000006) and TTP (P=0.000001) than patients who had the same response status but were assigned to receive a single autologous transplantation. Compared to Tx-1, Tx-2 significantly extended OS (P=0.04), EFS (P=0.000006) and TTP (P=0.000001) also among patients who failed Cr or nCR after receiving the entire treatment program to whom they were assigned (Tx-1 or Tx-2). At the opposite, for patients who were in CR or nCR after the first transplantation, there was no significant benefit from receiving a second autologous transplantation. In conclusion, data from the present analysis show that in comparison with a single autologous transplantation, i) double transplantation significantly prolonged EFS and TTP among younger (< 60 years) patients with previously untreated MM; ii) double autologous transplantation was of particular benefit for patients who failed at least nCR. Mature data derived from the final analysis of the study must be awaited before definite conclusions can be given concerning the impact of double autologous transplantation on the outcome of patients with MM. Supported by Università di Bologna, Progetti di Ricerca ex-60% (M.Cavo); Ministero dell’Università e Ricerca Scientifica, progetto FIRB, RBAU012E9A_001 (M. Cavo); and Fondazione Carisbo.

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The Clinical Impact of Macrofocal Disease in Multiple Myeloma Differs Between Presentation and Relapse

Blood ◽

10.1182/blood.v128.22.4431.4431 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4431-4431 ◽

Cited By ~ 2

Author(s):

Leo Rasche ◽

Amy Buros ◽

Niels Weinhold ◽

Caleb K. Stein ◽

James E McDonald ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Research Funding ◽

Low Risk ◽

Disease Stage ◽

First Line ◽

Focal Lesions ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction Functional imaging of Multiple Myeloma (MM) is redefining our knowledge of disease patterns. A pattern, termed macrofocal MM (macro MM), is defined by the presence of focal lesions and the absence of significant intervening bone marrow (BM) infiltration. At presentation, macro MM constitutes a distinct disease entity likely being associated with a favorable prognosis, although current evidence to support this is limited. Following first-line therapy, macrofocal patterns of disease emerge also in patients that initially presented with classical MM. In these patients the systemic BM involvement disappears in follow up examinations during treatment whereas focal lesions persist. In a third scenario, macrofocal patterns occur at overt relapse representing a patchy type of MM progression (Figure 1). The prognostic impact of a macrofocal pattern at these various disease stages is largely unknown. Therefore, we analyzed the clinical outcome and biological features of macro MM at different treatment stages. Patients and Methods 279 patients met the criteria of macro MM. Of those, 56 were at initial presentation, 48 at restaging following first line therapy, and 175 at relapse. Generally, macrofocal lesions were present in both positron emission tomography and magnetic resonance imaging. All first-line patients were treated with multi-agent induction therapy, autologous stem cell transplantation and received maintenance within prospective trials. Outcome results were compared to a set of cases with classical MM matched for age, gene-expression based (GEP) risk group, and treatment protocol. Results Macro MM at presentation is rare, constituting 6% of patients in the time period examined. The vast majority showed GEP-based low risk (94%). Age, Ig-type, and sex were not significantly different between macro MM and classical MM. With a median follow up of 8.6 years, only 10 of the macro MM patients relapsed. Compared to a matched-pair MM group, progression-free survival (PFS) and overall survival (OS) were significantly better in the macro MM group (P= 0.01 and 0.04 for PFS and OS, respectively). Thus macro MM at presentation constitutes a low risk form of MM. Focusing on the 10 macro MM cases who relapsed, no specific risk profile could be identified except >26 focal lesions on MRI was associated with a shorter PFS (P=0.04) but not with OS. Of note, although focal lesions frequently responded slowly, the time to response was not associated with outcome. To elucidate whether there are biological differences between MM cells in focal lesions and at differentially involved BM sites, we analyzed a set of 16 patients with paired samples from macrofocal lesions and iliac crest BM aspirates. No difference in a GEP based proliferation index was seen between the two sites. After correction for multiple testing we did not observe gene expression differences between them. A candidate gene study including a set of 27, myeloma relevant, adhesion molecules also did not reveal expression differences. In contrast to the situation at presentation, macrofocal patterns at restaging during initial therapy showed a 70% cumulative 24 months relapse incidence. The outcome of these cases was significantly worse in comparison to matched controls (P=0.02 and 0.02 for PFS and OS, respectively). Of note, all patients with macro MM showed an objective response at the time of imaging with 9 of 46 cases meeting the IMWG criteria for CR. Performing a similar analysis of patients with macro MM at relapse showed that 25% of patients presented with that pattern; a surprisingly high proportion. Extramedullary involvement was common (41%). Of note, 36% of patients repeatedly showed macrofocal patterns at subsequent relapses. PFS and OS at 2 years from macrofocal relapse were 24% and 39%, respectively. A matched group OS comparison was not possible since number of relapses and treatments were too different among the patients. Conclusions Macro MM at presentation seems to be an early stage of MM with an excellent prognosis. In contrast, a macrofocal pattern at restaging is associated with poor prognosis and early relapse. At this disease stage residual focal lesions may represent drug resistant clones. At overt relapse a macrofocal pattern was frequently seen, highlighting the need to integrate advanced imaging tools into the standard work up and indicating an important confounder of standard minimal residual disease diagnostics in MM. Disclosures Barlogie: Signal Genetics: Patents & Royalties. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment.

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