ALBERT

Description: Rapid eradication of blasts from peripheral blood during induction therapy in AML is associated with remission and overall survival. We prospectively evaluated the value of a bone marrow (BM) examination on day 5 of induction therapy in unselected newly diagnosed AML patients assigned for intensive induction. Seventy nine patients were enrolled during a 29-months period in six medical centers in Israel. BM blasts were evaluated by two independent observers and in most cases with the support of FACS analysis. Induction protocols administrated were 3+7 with daunorubicin 60 or 90 mg/m2 or clofarabine 40mg/m2 for five days [58 (73%), 10(13%) and 11(14%) patients, respectively]. Patients’ median age was 59 (range 22-78) years. Among surviving patients the actual follow-up time was longer than 9 months in 25(48%) patients and longer than 12 months in 16 (30%) patients. Cytogenetic results are available for 70 patients [2(3%), 47(67) and 21(30%) with standard, intermediate and poor risk, respectively]. Flt3ITD mutation was present in 11(13.9%) patients and NPM1 mutation, in 12 who presented with normal karyotype and were negative for FLT3-ITD. Treatment protocol was not altered on the basis of day 5 BM examination which was repeated on day 12-14. Residual disease (〉10% blasts) was detected and a re-induction protocol (repeat 3+7 at doses of 60 or 45mg/m2 at day 14 or clofarabine 30mg/m2 on day 21) was administered in 20(25%) patients. Overall, 50(72%) patients achieved remission (CR1). Post-remission therapies varied according to patient age and risk factors. Overall, 29(37%) patients underwent allogeneic stem cell transplantation. During the study period, 27(34.2%) patients succumbed, 5(6.3%) during induction, 8(10%) while in remission and 12(15%) following relapse. Day 5 blast counts higher than 10% of all BM nucleated cells predicted for the identification of residual leukemia on day 14 regardless of BM cellularity. Moreover, day 5 counts lower than 10% of all BM nucleated cells predicted for the achievement of CR1 with a single induction course. The 10% cutoff for BM day 5 blast count accurately identified these patients with a sensitivity of 80% and specificity of 74%. Kaplan Meir analysis demonstrated superior overall survival (OS) and lower relapse rate (figure 1a&b) of rapid responders than those with more than 10% blasts in day 5 BM. The 2-year anticipated OS is 80% and 35% (p=0.05), respectively. For the 50 patients who achieved CR1, the predicted 2-year relapse rate was as low as 8% for patients with a low day 5 BM blast count and 82% in the group of higher day 5 BM blasts (p=0.004).Figure 1Figure 1. Bone marrow day 5 aspiration was not always informative and in seven cases where biopsy was not available the blast content couldn’t be assessed. Of the 72 patients with a valid day 5 blasts count, 24 (33%) were rapid responders in whom blasts were less than 10% of BM nucleated cells. On day 14, a lower than 10%, blast count was recognized in 54% of patients. However, 11/16 (69%) of patients who despite high blast counts at day 5 had a low count at day 14, either failed to achieve remission or relapsed. Only 5 patients presented with a low blast count at day 5 had a day 14 blasts count higher than 10%. Rapid response on day 5 was not associated with age or molecular status; yet, there was a trend (p=0.08) towards lower frequency of poor cytogenetics among these patients. Surprisingly, mean presenting WBC was higher among rapid responders. Conclusion Bone marrow blast count on the fifth day of induction during chemotherapy is a powerful predictor of AML prognosis, irrespective of other pre-treatment risk factors. Larger studies, with longer follow up are required to determine its role in clinical management. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4824 Background: HL and NHL have traditionally been considered as two distinct entities. However, there have been reported rare cases of patients that over time develop both diseases. It is an unresolved issue whether the origin of the two diseases is from the same clone. The literature is replete with anecdotal reports but it has never been prospectively or retrospectively evaluated in consecutive patients from a large series. In this study we attempted to retrospectively investigate this phenomenon by reviewing the clinical and molecular aspects of a group of patients who developed both lymphomas. Although not absolutely definitive, a differing gene rearrangement (GR) pattern is currently thought to be highly suggestive of a different clonal origin. Methods: Study patients were all patients treated at the Hadassah University Medical Center, Jerusalem, Israel, who developed both kinds of lymphoma throughout their lives and were treated for at least one of the lymphomas during the period 1989–2010. The clinical and pathologic records of these patients were reviewed. Archival, formalin fixed, paraffin embedded tissue samples from all the patients that had available samples from both diseases were obtained. The rearranged immunoglobulin heavy-chain variable region genes from both diagnoses were amplified by polymerase chain reaction (PCR) and were compared to each other. Results: There were 26 patients who presented with two diagnoses. Twelve had HL as the primary disorder and the majority of these (75%) presented with aggressive lymphoma as the second lymphoma. The mean survival from the second lymphoma was 4.06 years. Five patients are still alive. In contrast, in the 11 patients where NHL was the primary disorder, this was usually (82%) of low grade histology. The mean survival in this case was 2.16 years. Four patients are still alive. Three patients were diagnosed concurrently with both diseases. For 11 patients there were available diagnostic samples for molecular analyses from both diagnoses of HL and NHL. In 6 of these 11 patients gene rearrangement studies were informative providing data for both diagnoses. The same GR was not found in any of the 6 patients. DLBCL=Diffuse Large B Cell Lymphoma, CLL/SLL=Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, marginal=marginal zone lymphoma, low grade=low grade B cell lymphoma unspecified Although the numbers are small, these data suggest that it is likely that in the case of two different lymphoproliferative disorders they are of separate clonal origin. Conclusions: The development of HL and NHL at different time points should be assumed to be a different biologic disease, until proven otherwise. Disclosures: No relevant conflicts of interest to declare.

Description: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse 〉 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses〈 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse 〉 3 yearsRelapse 〉 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

Description: Introduction Improvement in overall survival (OS) is seen primarily within standard risk Multiple Myeloma (MM), however, high risk MM OS was still around 2-3 years until recently. Del17p is a genomic imbalance which includes deletion of the TP53 locus. It occurs in ~7-10% of MM at diagnosis and is associated with extramedullary disease and is a strong poor prognostic factor. Recently approved novel agents and combinations have demonstrated improved outcomes also in patients with negative cytogenetic features; however, their long term impact remains to be seen. Access to newer agents depends on time of diagnosis as well as availability of clinical trials, access programs and insurance coverage. The goal of this study is to analyze real world data including treatment patterns and outcomes among MM patients carrying 17p deletion, in a retrospective multi-site study. Methods An observational, retrospective, multi-center study. Consecutive patients diagnosed with multiple myeloma in the 8 participating centers in Israel, diagnosed between 1.1.2008 - 3.1.2016 that were proven to carry 17p deletion by means of FISH studies (any % of plasma cells), were identified by searching hospital records including cytogenetic lab records. Data concerning patient demographics, disease characteristics, treatment regimens and clinical endpoints were collected. Results A total of 57 patients carrying 17p deletion of FISH were identified. Patient's characteristics are described in table. Notably, most patients had bone disease; extramedullary disease (EMD) rate was relatively high, as was the presence of additional high risk FISH abnormalities. Most patients received a bortezomib-based induction, over half underwent ASCT. Fifteen (26%) of the patients participated in clinical trials or access programs (or both) (table). Overall response rate (ORR) after induction was 84%, response rate declined in subsequent treatment lines (figure 1). The median follow-up was 21 (range, 4-94) months. Median overall survival (OS) was 43 months; Median Progression free survival (PFS) was 20 months (figure 2A,B). In univariate analysis, presence of extra-medullary disease at diagnosis was associated with worse PFS (7.4 vs. 21.4 months, p=0.05, figure 2C); presence of additional high risk FISH findings also trended towards shorter PFS (13.5 vs 21.4 months, p=0.0569), while age, gender, ISS, %plasma cells, % cells with del17p, time of del17p detection, M-Spike and iFLC levels were not significantly associated with PFS. Among patients with a PFS greater than 6 months, ASCT was associated with a significant improvement in PFS (25.7 vs 9.0 months, p=0.0022 log-rank test) (figure 2D), 4 patients underwent allotransplant, with a median OS of 69 months. Conclusions Our data confirm the poor prognosis of myeloma patients with del17p, in a multi-site observational setting, and an even worse prognosis in the presence of extramedullary disease and additional high-risk FISH features. While ORR after induction is similar to that generally expected in a newly diagnosed myeloma patients, responses are shorter and thus PFS is inferior compared to recently reported upfront bortezomib-based regimens ranging from 30-40+ months. Responses decline further in subsequent lines yet remain non-negligible even in advanced therapeutic lines. Our data support the role of ASCT in these high risk patients, and the potential role of allotransplant in selected patients. High rate of participation in clinical trials and access programs throughout the course of therapy reflects the valued role of newer agents in the management of myeloma patients. Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

Description: Background Extramedullary disease (EMD) of acute myeloid leukemia (AML) was described decades ago but the incidence of this phenomenon and its prognostic impact are not clear. It is also uncertain whether every site of EMD has the same significance. This study explored these questions using a large cohort of AML patients treated on consecutive Eastern Cooperative Oncology Group (ECOG) frontline clinical trials. Methods For AML patients enrolled into ECOG clinical trials, the presence of EMD was captured at baseline on case report forms. From patients with newly diagnosed AML, age 15 and above, who were treated on 11 consecutive different clinical trials, we identified those with or without EMD, defined by physical examination, laboratory findings and imaging, without necessarily a biopsy. We used descriptive statistics to summarize patient and disease characteristics. Univariate analyses of potential prognostic factors were done. The Kaplan-Meier method was used to estimate median overall survival (OS) within each prognostic category and differences were explored using the log-rank test. Cox proportional hazards models were used to examine the effect of one-unit increases in continuous variables on OS and for multivariable analyses. Multivariate models were built using backward selection. Factors (or groups of factors) significant at the 0.10 level in univariate analyses were tested for inclusion in the model, and retained if they were significant at the 0.05 level. Results Of the 3,522 patients enrolled in 11 different AML clinical trials, we excluded 281; for diagnosis of other types of leukemia (n=220), no EMD evaluation at baseline (n=41) or no survival data (n=20). The overall incidence of EMD was 23.8% (770 out of the remaining 3,241 patients). The sites involved were: lymph nodes 367 (11.3%) patients, spleen 234 (7.2%), liver 173 (5.3%), skin 146 (4.5%), gingiva 104 (3.2%), central nerve system (CNS) 32 (1%), peripheral nerve system (PNS) 8 (0.2%) and other sites 134 (4.1%). In 65 cases (8.4%) EMD was confirmed by biopsy. Most of the patients (64.4%) had only one site of EMD, 163 (21.2%) had 2 sites, 75 (9.7%) - 3 sites, 28 (3.6%) - 4 sites, and 4 patients (0.5%) each had 5 or 6 sites. EMD patients compared to those without EMD; tend to be younger (median age 45.7 vs 52.9 years); male (57.7% vs 52%); poorer ECOG performance status (76.4% with ECOG 0-1 vs 85.9%) and with higher white blood cell count (WBC) at diagnosis (median of 41.6/µl vs 10.2/µl). In univariate analysis, having EMD was associated with a shorter OS (P=0.006). Examination of individual EMD sites revealed that skin (P=0.002), spleen (P=0.0002) and liver (P=0.0007) but not CNS (P=0.35), PNS (P=0.53), nodal involvement (P=0.85) and gingival hypertrophy (P=0.14), were associated with poorer OS. Using proportional hazards models for continuous factors, each additional site of EMD conferred a 9.4% increase in the risk of death. In a multivariable model, after adjusting for known prognostic factors (such as: age, WBC count and cytogenetic risk group), the presence of EMD, number of EMD sites and any specific EMD site were not independently prognostic. Of 165 patients with known favorable cytogenetics EMD was present in only 22 patients (13%). This group appeared to have a worse prognosis, but the numbers are too small for a definitive assessment (figure 1). Conclusions Extramedullary disease is common in newly diagnosed AML with an incidence of almost 24%, but CNS involvement is very rare (0.95%). In contrast to published data, no site of EMD was found to have an independent prognostic impact in multivariate analysis. This large dataset emphasizes the importance of evaluating large number of patients and considering all known risk factors in the multivariate analysis. Disclosures: No relevant conflicts of interest to declare.

Description: (Introduction) Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare but life-threatening stem cell disease caused by expansion of PIGA mutated clone(s). PIGA mutation abolishes the expression of GPI-anchored proteins on the cell surface including CD55 and CD59 which protect red blood cells from complement attack, resulting in complement-mediated destruction of PNH erythrocytes. Eculizumab (Ecu) effectively ameliorates the intravascular hemolysis in PNH patients by blocking complement C5 in the terminal pathway. We previously reported that 3-4 % of the Japanese patients did not respond to Ecu due to C5 polymorphism c.2654G〉A (predicting p.Arg885His) and one Argentina patient with similar but different polymorphism c.2653C〉T (predicting p.Arg885Cys) (N Engl J Med 370:632, 2014). Since then, we have received various consults regarding poor response cases and requests for analysis from around the world. Here, we summarize the latest series of analyses in C5 polymorphisms and propose optimal management based on these findings. (Method) Once poor response to Ecu, defined as sustained high serum LDH, was suspected with sustained high serum LDH level, peripheral blood samples with clinical data were sent to our institute after obtaining patients' informed consent. DNA was extracted from the samples, and the hot spot of C5 polymorphisms at exon 21 was sequenced by Sanger method. If no polymorphism was identified, all 41 exons of C5 were sequenced. (Results) At the initial publication (2014), 11 cases of c.2654G〉A were identified out of 345 PNH patients (3.2%). As of July, 2018, a total of 22 patients were identified among roughly 600 patients treated with Ecu in Japan (3.7%). To determine the distribution of the polymorphism, a DNA panel containing 120 Han Chinese persons were previously screened, and one had the polymorphism. The same C5 polymorphism was newly identified in one among 89 patients treated with Ecu in Korea. A similar polymorphism c.2653C〉T (predicting p.Arg885Cys) was also previously identified in an Argentina patient. Another polymorphism c.2653C〉A (predicting p.Arg885Ser) was identified in a Dutch patient. Furthermore, a novel mutation c.2422 G〉A (predicting p.Val 808 Ile) was found in a poor responder in Israel, and currently under functional analyses. (Discussion) In PNH patients treated with Ecu, serum LDH level usually drops importantly after the first loading dose, and mostly comes to upper limit of normal range after second or third loading dose. If the serum LDH level remains high, poor response should be considered. CH50 is usually not detected in Ecu responsive patients, so monitoring of CH50 level is critical to evaluate the responsiveness to Ecu. Once poor response is suspected, hot spot of exon 21 should initially be sequenced, and then the whole 41 exons of C5 may need to be sequenced. c.2654G〉A was found among Han　Chinese in our previous study, so it is reasonable that a Korean case had the same polymorphism considering the geography. Surprisingly, a Caucasian case with the same polymorphism has been reported (Blood Advances 1:1254, 2017) in addition to the Dutch case, underlining the importance of poor responsiveness due to polymorphisms (p.Arg885) even outside of Asia. We previously reported that Coversin, a C5 inhibitor derived from tick saliva protein, blocked hemolysis in vitro using the serum from the patients with c.2654G〉A, and it was reported that post-transplant thrombotic microangiopathy was successfully treated with Coversin for the patient with the polymorphism (Blood Advances 1:1254, 2017). C5 inhibitors targeting a different epitope or having different mechanisms from Ecu as well as other upcoming complement inhibitors targeting Factor D or C3 are expected to benefit patients with C5 polymorphism and resistance to Ecu. Further analyses and clinical trials may pave the way to a second generation anti-complement drug to treat PNH patients. Figure. Figure. Disclosures Ueda: Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Muus:Akari Therapeutics: Consultancy. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Nishimura:Chugai Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Kanakura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Description: The diagnosis of venous thromboembolism (VTE) is being done by imaging studies but can be ruled out by clinical probability assessment together with a D-dimer blood test. Thromboelastogram (TEG) is usually used for the evaluation of bleeding tendency but can demonstrate also hypercoagulable states. Our hypothesis was that TEG may estimate the presence of VTE more accurately than D-dimer. This prospective study recruited patients that presented to the emergency room or to the vascular laboratory with signs/ symptoms that raise the suspicion of acute VTE. TEG parameters that were examined were: Reaction time(R), Clot time formation (K), Alpha angle (α), Maximal amplitude (MA), Clot viscoelasticity (G), Coagulation Index (CI) and Clot lysis at 30 minutes (LY30). The expected values for hypercoagulable state include: short R and K and high α, MA, G, LY30 and CI. Between April and October 2016, a total of 109 patients were enrolled in the study with a median age of 55.7 (21-89) years. Their characteristics are summarized in table 1. Forty-eight percent of the patients had at least one risk factor for development of VTE. According to the Well's criteria, 54 (49.5%) patients had low probability, 46 (42.2%) - moderate and 9 (8.3%) - high probability for developing VTE. Eighteen patients were diagnosed with VTE; 12 with DVT, 7 with PE and one with both. Analyzing the different TEG parameters, both as continuous (table 2) or categorical variables (according to their normal range), did not reveal a statistically significant difference between VTE positive and negative patients. Combining different TEG parameters or dividing the cohort according to: gender, clinical suspicion of VTE based on the Well's criteria or different levels of D-dimer did not change the results of the analysis. In conclusion, the current study could not demonstrate a significant value of any TEG parameter as a predictor of VTE in a general population of patients who came to the emergency room or vascular laboratory with signs/ symptoms that raise the suspicion of VTE. Disclosures No relevant conflicts of interest to declare.

Description: The identification of mutations in BRAFV600E and other kinases in systemic histiocytoses changed our understanding of the pathophysiology of these disorders from inflammatory non-malignant conditions to clonal disorders driven by altered MAP kinase signaling. In addition, BRAFV600E mutations have recently been noted in bone marrow (BM) CD34+ cells of patients with Langerhans Cell Histiocytosis (LCH), suggesting that LCH represents a clonal disorder arising from hematopoietic stem/progenitor cells (HSPCs). However, it is unknown if HSPCs from LCH or other histiocytoses patients can functionally give rise to these disorders. Moreover, whether or not patients with histiocytosis have additional hematological disorders related to the presence of HSPC-based mutations is unclear. Here we attempted to understand the spectrum of hematological disorders in patients with histiocytoses and the cell-of-origin of histiocytic neoplasms by functionally analyzing HSPCs from histiocytoses patients. We first analyzed a multicenter cohort of 190 adult histiocytoses patients. This unexpectedly identified a high frequency of patients with a co-existing myeloid malignancy. Of the 190 patients, 9.5% (18/190) were diagnosed with Erdheim-Chester Disease (ECD) and/or LCH concomitantly with a classic MPN (3.7%; 7/190), MPN/MDS overlap (4.7%; 9/190), or MDS (1.1%; 2/190) (Figure). This clinical observation was confirmed by detection of co-existing histiocytoses-associated kinase mutations (including BRAF, MAP2K1, NRAS, or KRAS mutations) with JAK2 or CALR mutations, as well as other mutations recurrently found in myeloid malignancies (such as IDH1/2, ASXL1, and TET2 mutations (Figure)). These data therefore reveal a heretofore-unrecognized clinical overlap of adult-onset systemic histiocytoses and WHO-classified myeloid malignancies while further highlighting the possibility of an aberrant HSPC origin for histiocytic neoplasms. In most cases, the BRAF/MAP2K1/RAS mutation predominated in the histiocytic lesion while the JAK2/CALR mutation predominated in the BM/peripheral blood suggesting likely distinct clones driving each clinical condition. Next, to test the self-renewal and differentiation capacity of HSPCs from histiocytoses patients, CD34+ cells were purified from 8 patients including 6 with ECD or LCH plus a concomitant myeloid neoplasm, and 2 with ECD alone. 0.1-0.8x106 CD34+ cells from each patient were transplanted by intrafemoral injection into sublethally irradiated NOD/SCID IL2Rγ transgenic human GM-CSF, IL-3, and SCF expressing (NSG-SGM3) mice. Human engraftment was monitored by monthly flow cytometric analysis of peripheral blood until mice became moribund. Thereafter, animals were sacrificed and tissues were analyzed using flow cytometry, histology, immunohistochemistry, and sequencing analyses to detect driver mutations identified in the histiocytosis/co-occurring myeloid neoplasm. Successful engraftment of human myeloid cells was verified in grafts generated from 2/8 patients after a mean of 90 days (range: 60-120 days). This included lethal engraftment of KRAS-mutated ECD patient cells at 90 days manifested by infiltration of human hCD45+ cells co-expressing human myeloid and monocyte lineage markers hCD33 and hCD14 in the bone marrow, spleen, liver, lung, and kidney (Figure). Immunostains revealed that tissues were infiltrated by an hCD45+hCD163+hCD68+ population of foamy histiocytes, characteristic of ECD (Figure). Furthermore, genomic analysis of DNA from the engrafted animals BM and spleen revealed the same KRASG12S mutation found in the donor patients ECD lesion. Engraftment of a patient diagnosed with concomitant BRAFV600E-mutant ECD and ASXL1/TET2-mutant CMML was seen at 60 days. In this case, however, only engraftment of human CMML was detected without evidence of the BRAFV600E-mutant ECD component. This study suggests that adult histiocytic neoplasms frequently co-occur with other myeloid neoplasms. Moreover, histiocytosis disease-driver mutations are present in the CD34+ HSPCs, which we show for the first time can initiate disease that resembles human histiocytosis in a patient-derived xenograft. Importantly, however, even though the CD34+ compartment gives rise to both the histiocytic and myeloid neoplasm disease component, each disease is likely initiated by distinct precursors. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Despite its favorable prognosis, 10-20% of APL patients relapse with contemporary therapeutic strategies. At relapse, reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). In the last two decades, arsenic trioxide (ATO) has become part of the standard reinduction regimens. Such an approach is often followed successfully by auto-HCT. However, long-term survivors have also been reported after ATO treatment alone without HCT. We retrospectively compared the outcome of auto-HCT, with or without ATO, and ATO-based therapy given alone following relapse in patients with APL. Patients and Methods: Data on APL patients in first relapse were collected from the two largest transplant registries (CIBMTR, EBMT) and two specialty referral centers (Hematology-Oncology & Stem Cell Transplantation Research Center, Shariati Hospital, Tehran and Christian Medical College & Hospital, Vellore, India). The outcome of patients who received ATO at relapse and did not undergo transplantation was compared to that of patients who received any reinduction therapy, including ATO and subsequent auto-HCT. Overall survival was calculated from two months post relapse with left truncation at date of CR2 for patients receiving ATO alone and date of transplant for those receiving auto-HCT. Cox proportional hazard regression was used to estimate the univariate and multivariate associations with overall survival. Potential prognostic factors included age, disease risk based on WBC 〉10,000/µl, the presence of extramedullary disease, and duration of CR1, in addition to the primary comparison of auto-HCT and ATO-based reinduction therapy. Results: 242 patients were identified, of whom 34 were excluded due to missing relapse date (n = 25), death or lost to follow-up before 2 months after relapse (n = 7), or receiving auto-HCT within two months of relapse (n = 2). The median age was 31, 63% of the patients were males and median WBC count at diagnosis was 4,750/µl. The final cohort of 208 patients included 68 receiving ATO alone and 140 receiving auto-HCT. The groups were comparable in terms of age, gender, duration of CR1 and risk group. Fifty-six percent of the auto-HCT patients received ATO-based treatment as salvage therapy and the others received various combinations of chemotherapy and ATRA. There is a statistically significant survival advantage for the HCT group (HR = 0.34 (0.27-0.42), p