Abstract: BCR-ABL negative myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are chronic myeloid malignancies characterized by overproduction of hematopoietic cells. JAK2 mutations are found in most patients with PV, and in only 50-60% of patients with ET and MF. JAK2 mutation testing has greatly simplified MPN diagnosis, but distinguishing JAK2-wildtype ET from reactive thrombocytosis remains a diagnostic challenge. Mutations in signalling pathways (MPL, LNK) and epigenetic regulators (TET2, DNMT3A, IDH1/2, EXH2, ASXL1) have been found in a minority of MPNs. However genome-wide data are lacking and the pathogenesis of MPNs that do not harbor JAK2 or MPLmutations remains obscure. Methods Exome sequencing was performed in 151 MPN patients on matched tumor and constitutional samples. CALR status was assessed in 3412 samples using Sanger sequencing and analysis of exome/genome sequencing data. Presence of CALR mutations in hematopoietic stem and progenitor cells was assessed by flow sorting and sequencing. Phylogenetic trees were established using hematopoietic colonies. Calreticulin cellular localisation was assessed in patient samples and cell lines expressing CALR variants by flow cytometry and immunofluorescence. Results Exome sequencing identified 1498 somatic mutations with a median of 6.5 mutations in PV and ET, and 13 in MF (MF vs ET, P=0.0002; MF vs PV, P=0.008). JAK2V617F was found in all cases of PV (n=48), 56% of ET (35/62), and 69% of MF (27/39), and MPL mutations in 7 ET and MF cases.  Mutations in epigenetic regulators TET2, DNMT3A, ASXL1, EZH2, and IDH1/2 were identified in 22, 12, 12, 4, 3 patients respectively, and components of the splicing machinery (U2AF1, SF3B1 or SRSF2) were mutated in 9 patients.  Mutations in rare genes reported to be mutated in MPNs were found in four patients (1 CBL; 2 NFE2; 1 SH2B3/LNK). We found novel somatic mutations in CHEK2 (1 PV, 1 ET and 1 MF) which have not been previously reported in MPNs.  The mutation spectrum showed a predominance of C 〉 T transitions. Pairwise associations between MPN genes demonstrated that ASXL1 and SRSF2 mutations were positively correlated with mutations in epigenetic modifiers. Novel somatic mutations in calreticulin (CALR) were identified by exome sequencing in the majority (26/31) of JAK2 or MPL unmutated patients. CALR and JAK2/MPL mutations were mutually exclusive, and 97% of patients harbored a mutation in 1 of these 3 genes. In an extended follow up screen of 1345 hematological malignancies, 1517 other cancers and 550 controls we found CALR mutations in 71% of ET (80/112), 56% of idiopathic MF (18/32), 86% of post ET-MF (12/14) and 8% of myelodysplasia (10/115), but not in other myeloid, lymphoid or solid cancers. Compared to JAK2-mutated MPNs, those with CALR mutations presented with higher platelet counts (Wilcoxon rank-sum, P=0.0003), lower hemoglobin levels (Student’s t test, P=0.02) and showed a higher incidence of transformation to MF (Fishers exact, P=0.03). All CALR mutations were insertions or deletions affecting exon 9, with 2 common variants L367fs*46 (52 bp deletion) and K385fs*47 (5 bp insertion). Loss of heterozygosity over CALR was seen in a minority of patients. Of 148 CALR mutations identified, there were 19 distinct variants. Remarkably, all generated a +1 basepair frameshift, which results in loss of most of the C-terminal acidic domain of the protein as well as the KDEL Golgi-to-endoplasmic reticulum (ER) retrieval signal, raising the possibility of compromised ER retention. Mutant proteins were readily detected in transfected cell lines and localised to the ER in the same manner as wildtype CALR, without Golgi or cell surface accumulation. These results are consistent with studies reporting KDEL-independent mechanisms of ER retention. Mutation of CALR was detected in highly purified hematopoietic stem/progenitor cells. Clonal analyses demonstrated CALR mutations in the earliest phylogenetic node in 5/5 patients, consistent with it being an initiating mutation in these individuals. Conclusions We describe the mutational landscape of BCR-ABL negative MPNs and demonstrate that somatic mutations in the endoplasmic reticulum chaperone CALR are found in the majority of patients with JAK2-unmutated MPNs. These results reveal a novel biological pathway as a target for tumorigenic mutations and will simplify diagnosis of MPN patients. Disclosures: Bowen: Celgene: Honoraria. Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract: The occurrence of late events [i.e. secondary malignancies (SM)] after therapy is of special relevance in patients with Hodgkin«s lymphoma (HL) as the median age of this population is quite low and first line therapy is curative in a high proportion of them. Autologous stem cell transplantation (ASCT) is the standard of care for patients with HL in first relapse and chemosensitive disease and for those patients who demonstrate to be primary refractory. The administration of chemotherapy +/- radiotherapy is a risk factor for the development of SM and, high dose chemoradiotherapy given as conditioning regimen before stem cell infusion can further increase this risk. In this retrospective study we have analyzed the incidence of SM as well as of the different subtypes [acute leukemias (AL) / myelodisplastic syndromes – myeloproliferative disorders (MDS-MPD), lymphomas and solid tumors (ST)] in more than 2000 HL patients undergoing an ASCT with a very long follow up after transplantation. 2261 patients with HL being treated with an ASCT between January/1985 and December/1995 and reported to the Lymphoma Database of the EBMT have been included in this analysis. There were 871 (38.5%) females and 1390 (61.5%) males with a median age at diagnosis of 26.8 years and at transplantation of 30.2 years. Median follow up for surviving patients was 9.1 years. Median time from diagnosis to ASCT was 26.6 months and 1989 patients (88% of the series) received at least 2 lines of chemotherapy before undergoing the autologous procedure. 694 patients were autografted in complete remission (CR) and the remaining 1567 with visible disease (amongst them, 279 patients had primary refractory disease, 458 patients sensitive relapse and 216, refractory relapse). Total body irradiation (TBI)-containing regimens only represented 4.2% of all conditioning protocols. 1300 patients were conditioned with BEAM / BEAM like protocols, 670 with CBV and 197 with other combinations. As expected because of the year of transplantation, bone marrow was used as the source of stem cells in 1407 patients (62.2%). After a median follow up of 10.5 years for all patients, 978 (45.4%) are alive and 1178 (54.6%) have died, 959 patients (43.7%) have relapsed after ASCT and 378 (17.5%) have died of non-relapse mortality (NRM). Relapse rate (RR) of the whole population of patients was 43.5%, 46.2% and 47% at 5, 10 and 15 years, respectively. NRM ranged from 14.6% to 19.8% at 5 and 15 years after ASCT, respectively. Disease free survival (DFS) was 41.9%, 36.5% and 33.2% at 5, 10 and 15%, respectively and finally, overall survival (OS) at 5, 10 and 15 years was 53.1%, 44.4% and 38.8%, respectively. 122 patients (5.4% of the series) developed a SM after ASCT. The most frequent ones were ST (49 patients – 40.2% of the series) followed by AL / MDS-MPD (26 patients – 21.3% / 23 patients – 18.8%), lymphomas (17 patients – 11.5%) and others (9 patients – 7.4%). 95 patients (78%) were in CR at the time of developing the SM and 27 patients (22%) had already relapsed after ASCT and being treated with additional chemotherapy. 30 patients with SM died of this late effect after ASCT (3% of NRM for the whole population of patients). In conclusion, the development of a SM after an ASCT represents a significant late effect in this big population of HL patients with a very long follow up, the most frequent ones being the ST that, as expected seem to develop later after transplantation than AL / MDS – MPD and lymphomas. The impact of prior therapy as well as other well know prognostic factors in the development of SM after ASCT is still unclear and needs to be better defined.SMSTAL / MDS - MPDLymphomas5-year CI2.4%0.3%1.7%0.1%10-year CI4.8%1.4%2.2%0.3%15-year CI7.7%3.2%2.5%0.4%20-year CI11.7%5.9%2.7%1.5%CI. Cumulative Incidence Disclosures: No relevant conflicts of interest to declare.

Abstract: Although the presence or absence of somatic mutations in the immunoglobulin variable region (IgVH) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVHmutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage,IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVHgenes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVHmutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.

Abstract: We analyzed lymphocyte morphology, histology, immunophenotype, immunoglobulin heavy chain (IgVH) gene mutations, and clinical course in 80 unselected patients presenting with circulating t(11;14) lymphocytes. Of the 80 patients, 43 had peripheral lymphadenopathy (nodal group), and histology confirmed mantle cell lymphoma (MCL) in all. There were 37 patients with no lymphadenopathy (nonnodal group); 13 of 37 had histology, all showing MCL. IgVH genes were unmutated in 28 (90%) of 31 nodal and 15 (44%) of 34 nonnodal cases (P = .0001); CD38 was positive in 32 (94%) of 34 nodal and 16 (48%) of 33 nonnodal cases (P & lt; .001); 41 (95%) of 43 nodal patients required immediate treatment compared with 18 (49%) of 37 nonnodal patients who had indolent disease (P & lt; .0001). Median survival (95% confidence interval) was 30 months (10-50) in the nodal group and 79 months (22-136) in the nonnodal group (P = .005). Mutation status did not statistically affect survival, but of 6 long-term survivors ( & gt; 90 months) all were nonnodal and 5 of 5 had mutated IgVH genes. Lymphocyte morphology was heterogeneous in both groups: typical MCL in 56 cases (34 nodal, 22 nonnodal), blastoid MCL in 8 cases (3 nodal, 5 nonnodal), and small-cell MCL in 16 cases (6 nodal, 10 nonnodal, P = .12). Matutes immunophenotyping score was 1 in 65 cases and 2 in 15 (8 nodal, 7 nonnodal). We find no evidence against a diagnosis of MCL in the nonnodal group and suggest that mutated IgVH genes may help identify patients with indolent disease.

Abstract: 80% of patients with CLL present with a lymphocytosis detected on a routine blood count. Many studies have identified risk factors for disease progression but there remains uncertainty about the magnitude of risk and which factors are most useful in determining this risk. To address this we have studied a cohort of 122 stage A0 patients who presented with a lymphocytosis and typical CLL immunophenotype before 1996 and whose CLL has either progressed or remained stable over a 10 year period. All patients were reviewed at least annually. Disease progression was defined as the need for anti-leukemic therapy, an increase in stage or a downward trend in haemoglobin or platelet count, progressive lymphadenopathy or splenomegaly or constitutional symptoms. Karyotypic data, from analysis of G banded metaphases derived fromTPA stimulated lymphocyte cultures, were available on all cases at diagnosis. CD38 and ZAP 70 expression were measured on DMSO frozen cells. VH gene usage and mutational status, and telomere length were assessed on frozen DNA samples, while interphase FISH for del 13q14, del 11q and 17p (ATM and p53 loss) and trisomy 12, was undertaken on fixed cell suspensions. All samples had been collected and stored at, or close to the time of diagnosis. 50 patients had progressive disease. Of the 72 patients with stable disease, the lymphocyte count remained below 20x109/l in 53 and rose with a lymphocyte doubling time of 〉 1 year in the remainding 19 (termed slowly progressive). In univariate analysis, a lymphocyte count of 〉 20x109/l, unmutated VH genes, high expression of CD38 (cut off 30%) and ZAP70, del 11q, abnormal presenting karyotype and short telomere length all predicted for disease progression. There was no difference in VH gene usage between the progressive and stable groups. Among the 107 patients for whom lymphocyte count, VH gene mutational status, CD38 and ZAP 70 expression are all currently available, the number of poor risk factors in the progressive and stable groups is shown in Table 1. There was no difference in the number of risk factors between the stable and slowly progressive groups. Del 11q was found in 9 progressive cases all of whom had 2 or more risk factors. P53 loss was found in a single patient with stable disease and no risk factors. 20/122 patients presented with a lymphocyte count 〈 5.0x109/l, below which patients have been considered to have monoclonal B cell lymphocytosis. Interestingly, 5 of these developed progressive disease. Using only the lymphocyte count, CD38 and ZAP 70 expression, Table 2 shows the risk of disease progression according to the risk factors present. In summary, once ZAP 70 measurement by flow cytometry is standardized, readily available prognostic tests can provide a quantitative estimate of the risk of disease progression. Performing interphase FISH for 11q and p53 loss in poorer risk cases only may provide additional prognostic information. Table 1 No. of adverse factors at presentation. (%) 0 1 2 3 4 Group Progressive 11(25) 10(23) 11(25) 9(20) 3(7) Stable/Slowly progressive 44(70) 16(25) 3(5) 0 0 Table 2 Odds of Progression % of Patients Progressing No risk factors 0.2 16.9 ZAP70 only 0.74 42.7 Lymphs 〉 20 0.89 47.0 CD38 only 1.57 61.1 ZAP70+lymphs 3.24 76.4 ZAP70+CD38 5.75 85.2 CD38+lymphs 6.85 87.3 All 25.1 96.2

Abstract: Flu/Cy/ATG and Cy/ATG regimens offer the best survival for matched-sibling BMT. Transplantation in patients aged ≥30 years is associated with higher mortality after matched-sibling and unrelated donor BMT.

Abstract: Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation–specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.

Abstract: We report the results of a phase I clinical study using a radiolabelled murine anti-CD66 IgG1 monoclonal antibody (TheraPharm GmbH) as part of the transplant conditioning schedule for patients receiving either autologous or allogeneic stem cell transplants (SCT) for myeloma or acute myeloid leukaemia. This was a radiation dose escalation study using increasing doses of yttrium-90 (Y-90) as the therapeutic radionuclide. A total of eighteen patients have been treated over four Y-90 radiation dose levels. All patients received an initial infusion of indium-111 (In-111)-labelled anti-CD66 for biodistribution and dosimetry determination. If favourable dosimetry was demonstrated, patients went on to receive the therapy dose of radiation, the dose of Y-90 infused calculated from the patient’s body weight. The Y-90 dose levels were as follows: 5, 10, 25 and 37.5MBq /kilogram (lean) body weight. Patient characteristics: Age 21-67 yrs (median 54 yrs); 14 male, 4 female; myeloma 14, AML 4; autologous SCT 14, reduced intensity allogeneic SCT 4. Patients undergoing autologous SCT for myeloma received Y-90 labelled anti-CD66 on day -14 and melphalan 200mg/m2 on day -2. Patients undergoing reduced intensity allogeneic SCT received Y-90-labelled anti-CD66 on day -14 in addition to a reduced intensity schedule of fludarabine, melphalan and CAMPATH 1H. Results: Excellent bone marrow targeting was seen in all patients and in the majority low uptake by non-haematopoietic organs, in particular liver uptake was consistently low. There was a close correlation between the administered dose of Y-90 and the dose delivered to the bone marrow but not for the radiation dose received by the liver. Mean absorbed radiation doses (cGy per MBq infused Y-90): bone marrow 10.23 +/- 1.8 cGy/MBq; liver 2.67 +/- 2.0 cGy/MBq; spleen 7.10 +/- 3.75 cGy/MBq. Total absorbed radiation doses at each dose level are in table 1. Table 1 Organ dose in Gy Dose level MBq per kg BM Liver Spleen 5 4.1 1.4 1.1 10 9.1 1.3 2.4 25 15.6 3.7 12.6 37.5 22.0 7.8 5.3 No additional toxicity due to the addition of targeted radiation was seen. Engraftment: neutrophils 〉 0.5 by day + 13.8 (11-22) platelets 〉 50 day +12.7 (10-22), no graft failures were seen. In two patients with myeloma, focal uptake of In-111-labelled antibody was seen suggesting in vivo targeting of myeloma, consistent with the expression of the antigen on plasma cells demonstrated by Flow cytometry. Conclusions: The anti-CD66 monoclonal antibody showed consistently excellent BM targeting and very low uptake by non-haematopoietic organs. Up to 25 Gy of additional radiation was delivered to the bone marrow with no additional toxicity. This particular monoclonal antibody may have a role in stem cell transplantation for a wide range of haematological malignancies, providing significant dose escalation without toxicity in autologous and allogeneic protocols. AntiCD66 may be particularly appropriate in transplantation for myeloma.

Abstract: Introduction: Prior to effective novel agent (NA) approval for CLL, alloHSCT was recommended for CLL patients (pts) with early relapse/refractory disease after purine-analogs or deletion 17p (del17p) or TP53 mutation (TP53mut) based on expert consensus and retrospectively demonstrated overall survival (OS) advantage. Since 2014, approvals of ibrutinib (ibr), venetoclax (ven), and PI3K inhibitors (PI3Ki) have led to fewer alloHSCT for CLL. While NAs are indisputably effective, many pts will eventually progress through all available NAs. In the absence of data-driven consensus regarding role of alloHSCT for CLL, decision about proceeding to transplant is currently based on disease and transplant risk, response to NAs, and pt preference. This study of CLL pts who underwent alloHSCT following NA therapy (tx) aimed to help define the role of this potentially curative modality in the era of NAs. Methods: This multicenter, retrospective cohort study examined CLL pts who underwent alloHSCT following treatment with ≥ 1 NA, including baseline clinical, prognostic, and transplant characteristics, tx preceding alloHSCT, transplant outcomes, and tx following alloHSCT. Complex karyotype (CK) and CLL status [complete remission (CR), partial remission (PR), stable disease (SD), and progression of disease (POD)] were defined per iwCLL criteria (Hallek, et al. Blood 2018) . Univariate analyses utilizing COX regression evaluated association between pre-alloHSCT factors and progression free survival (PFS). PFS, OS, and non-relapse mortality (NRM) were estimated using Kaplan Meier and life table methods. Other statistics were descriptive. Results: 69 pts with CLL underwent alloHSCT following ≥ 1 NA across 14 US and EU centers, including 6 pts with Richter's transformation (RT) prior to alloHSCT. Table 1 describes baseline characteristics. Prior to alloHSCT, 78% received ibr (n=53), 39% ven (n=25), 20% PI3Ki (n=13), and 36% ≥ 2 NAs. 90% (n=62) received a NA immediately preceding alloHSCT [n=32 ibr (16% CR, 75% PR, 9% SD/POD), n=25 ven (52% CR, 40% PR, 8% SD/POD), 4 PI3Ki (75% PR, 25% SD/POD), 1 IMiD]. With a median (med) follow up 28 months (mo; range 1.2 -85), med PFS and OS from alloHSCT for the entire cohort were not reached (Figure 1A, B). PFS and OS for pts with CLL (excluding RT pts) from alloHSCT were 60% and 82% at 24 mo respectively. Poor risk disease characteristics (TP53mut, del17p, CK), prior NA exposure (ibr, ven, PI3Ki, ≥2 NAs), and transplant characteristics (matched (8/8) vs. mismatched ( 〈 8/8) donor, positive CMV serology) were not associated with inferior PFS (Table 2). NRM was 3.4% at D+100, 8.9% at 12 mo, 10.4% at 24 mo. Acute graft-vs-host disease (GHVD) was observed in 52% (med onset = D+49); moderate-severe chronic GVHD occurred in 26%. Fifteen deaths (22%) were observed due to POD (n=6), infection (n=7), GVHD (n=2). 21 pts relapsed following alloHSCT; post HSCT pts were treated with ibr (n=6), ven (n=6), rituximab (n=3), R-CHOP (n=2), R-HyperCVAD (n=1), second alloHSCT (n=1). To guide decision making about timing of alloHSCT, we examined pts who received 1 (n=44) vs. ≥2 (n=25) NAs. These groups were similar in terms of poor risk features (del 17p 48% vs. 38%, TP53mut 44% vs. 40%, del11q 21% vs. 36%, CK 41% vs. 54%), transplant risk (med age 60 for both groups, med HSCT-CI 0 vs. 1, matched donor 86% vs. 71%), and disease status prior to alloHSCT (CR 25% vs. 40%, PR 66% vs. 48%, SD/POD 9% vs. 12%). PFS was similar for those exposed to 1 vs. ≥ 2 NAs (Figure 1C). Disease status at time of alloHSCT and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) significantly impacted PFS (Figure 1D, E). Conclusions: In the largest series of alloHSCT following NAs, data demonstrate that alloHSCT remains a viable curative strategy that can overcome adverse CLL characteristics including TP53 disruption and CK. As many pts treated with ibr and/or ven will progress or be intolerant, alloHSCT should be included in treatment algorithms for appropriate candidates. These data suggest that exposure to 1 vs. ≥2 prior NAs did not impact outcomes, though disease status at time of alloHSCT and HCT-CI are important predictors of PFS. Therefore, decision about proceeding to alloHSCT should consider comorbidities and current depth of response, as well as anticipated depth of response with the therapeutic options remaining. These data may significantly add to development of evidence-based guidelines for alloHSCT in the era of NAs. Figure 1 Disclosures Roeker: AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Brown:TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Dynamo Therapeutics: Consultancy; Sunesis: Consultancy; Juno/Celgene: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Catapult Therapeutics: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding. Eyre:Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Takeda: Other: Travel to Conferences ; Gilead: Consultancy, Other: Research support, Speakers Bureau; Janssen: Honoraria, Other: Travel to Conferences . Brander:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Tolero: Research Funding; Acerta: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; MEI: Research Funding. Skarbnik:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Coombs:H3 Biomedicine: Research Funding. Orchard:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Unrestricted educational award for regional meetings ; Incyte: Other: Unrestricted educational award for regional meetings ; Adienne: Other: Unrestricted educational award for regional meetings . Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; GSK: Consultancy. Giralt:Johnson & Johnson: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Kite: Consultancy; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Novartis: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Perales:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding.

Abstract: This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVHgene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutatedIGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutatedIGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVHgenes, unmutated IGVH genes, and loss or mutation of thep53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.