Citations

Abstract The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.

SummaryWe report a comparative analysis of patients with therapy‐related acute lymphoblastic leukaemia (tr‐ALL) vs de novo ALL. We identified 331 patients with B‐ALL; 69 (21%) were classified as tr‐ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr‐ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr‐ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease‐positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo‐haematopoietic cell transplantation.

Background: Thrombocytopenia is a frequently encountered laboratory abnormality and a common reason for hematology referrals. Workup for thrombocytopenia is not standardized and frequently does not follow an evidence-based algorithm. We conducted a systematic analysis to evaluate the laboratory testing and outcomes of patients evaluated for thrombocytopenia at hematology clinics in a tertiary referral center between 2013 and 2016. Patient and methods: We performed a comprehensive chart review for patients evaluated for thrombocytopenia during the study period. Patients were followed for 1 year from the initial hematology evaluation and assessed for the development of a hematologic malignancy, rheumatologic, or infectious diseases among other clinical outcomes. Results: We evaluated 472 patients with a median (range) age of 61 (17–94) years. The majority (63.8%) had mild thrombocytopenia. Within 1 year of follow-up, 14 patients (3.0%) were diagnosed with a hematologic malignancy. A higher likelihood of developing a hematologic malignancy was noted in patients with concurrent leukopenia (hazard ratio [HR] 9.97, 95% confidence interval [CI] 3.28–30.32, p < .01) and increasing age (HR per 10-year deciles 1.52, 95% CI 1.03–2.25, p = .03). In patients with asymptomatic isolated mild thrombocytopenia, laboratory testing did not reveal any significant positive findings and patients did not receive any new major diagnosis during the follow-up period. Conclusion: Our findings provide basis and call for development of an evidence-based algorithmic approach for evaluation of patients with thrombocytopenia, testing, and referrals. It also supports a conservative approach mainly driven by physical exam signs, symptoms, and other laboratory findings for patients with isolated mild thrombocytopenia.

AbstractDonor cell leukemia is a very rare cause of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Herein, we describe an unprecedented case of donor cell‐derived chronic myelomonocytic leukemia (CMML) presenting seven years after a 51‐year‐old man received a matched‐related alloHCT from his 59‐year‐old brother for T‐cell acute lymphoblastic leukemia.

Background There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. Methods A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. Results Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. Conclusions In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

Abstract Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

7523 Background: tALL is a recently appreciated but poorly defined clinical entity. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and we report a comparative analysis of characteristics, cytogenetics and outcomes for this subset among a modern unselected ALL cohort from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all patients (pts) diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) between 2008-2018. Comparisons of characteristics between tALL and dnALL were made using a Wilcoxon rank sum test (continuous variables) and Fisher’s exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 431 ALL pts were identified during the study period, including n = 69 (16%) classified as tALL. Median follow-up from diagnosis was 2.3 years (range 0-18 years). The most common prior malignancies among tALL pts were Breast (24.6%), Lymphoma (15.9%), Myeloid (15.9%), GU/GYN (14.5%) and Myeloma (11.6%). In comparison to dnALL, pts with tALL were significantly older (63.2 vs 45.2 years, P < 0.001), more often female (65.2% vs 39.8%, P < 0.001), less frequently Hispanic (3.5% vs 13.1%, P = 0.042); more often of B-lineage (92.8% vs 81.8%, P = 0.022). On review of cytogenetics, tALL pts more often had hypodiploidy/near triploidy (Ho/Tr) (21.7% vs 4.1%, P < 0.001), more often had monosomal (MDS-like) (33.3% vs 12.4%, P = 0.0047) and complex karyotype (38% vs 17.3%, P = 0.0069). Importantly, incidence of BCR/ABL-positive (Ph+) ALL was not significantly different. Latency period between exposure to prior cancer therapy and development of tALL was significantly longer for Ph+ compared to Ph-negative ALL (median 9 vs. 4 years, P = 0.007). Patients with tALL had a 3-year OS after diagnosis of 37% [vs 59.7% for dnALL (HR death 1.86, 95% CI 1.31-2.65, P < 0.001)]. However, the two groups did not differ significantly regarding occurrence of AlloHCT (HR = 0.91, 95% CI 0.63-1.31, P = 0.61) or post-AlloHCT survival (HR = 1.29, 95% CI 0.75-2.23, P = 0.35). Conclusions: Therapy-related ALL represents an important & unique clinical entity with poor prognosis & adverse cytogenetic features. Ph+ tALL has a longer latency and similar frequency in both tALL and dnALL. AlloHCT appears to be an appropriate treatment strategy, possibly abrogating the poor prognosis of tALL.

AbstractEsthesioneuroblastoma (ENB) is a rare olfactory malignancy that can present with locally advanced disease. At our institution, patients with ENB in whom the treating surgeon believes that a margin-negative resection is initially not achievable are selected to undergo induction with chemotherapy with or without radiotherapy prior to surgery. In a retrospective review of 61 patient records, we identified six patients (10%) treated with this approach. Five of six patients (83%) went on to definitive surgery. Prior to surgery, three of five patients (60%) had a partial response after induction therapy, whereas two of five (40%) had stable disease. Microscopically margin-negative resection was achieved in four of five (80%) of the patients who went on to surgery, while one patient had negative margins on frozen section but microscopically positive margins on permanent section. Three of five patients (60%) recurred after surgery; two of these patients died with recurrent/metastatic ENB. In summary, induction therapy may facilitate margin-negative resection in locally advanced ENB. Given the apparent sensitivity of ENB to chemotherapy and radiotherapy, future prospective studies should investigate the optimal multidisciplinary approach to improve long-term survival in this rare disease.

Introduction Novel high-risk groups have been identified in adult ALL, including secondary (sALL) and Philadelphia-like ALL (Ph-like, based on CRLF2, IgH, ABL2, JAK2 and other tyrosine kinase translocations), and those with minimal residual disease >0.1% (MRD+) after induction therapy. Novel targeted therapies are now routinely incorporated into 1st line regimens, including tyrosine kinase inhibitors (BCR-ABL1-pos), rituximab (CD20+) and blinatumomab (Blina) for MRD+. The impact of these novel high risk groups and therapies after alloHCT is unknown; therefore, we evaluated their impact on overall survival (OS), relapse rate (REL), non-relapse mortality (NRM) and acute and chronic GVHD. Methods We evaluated pts receiving 1st Allo-HCT for ALL at Mayo Clinic (Rochester, Phoenix, and Jacksonville) from 2008-2018 for outcomes of interest, specifically the impact of novel therapies and risk groups. Associations of patient factors with outcomes were examined using univariable (UVA) and multivariable (MVA) Cox proportional hazards regression models, where the cause-specific hazard of the given outcome was modeled to account for the competing risk of death. Results We identified 261 consecutive AlloHCT recipients during the study period. Median age at transplant was 48 years (18-72) and 147 (56.3%) were male. The median comorbidity (HCT-CI) score was 2 (0-8). 213 pts (81.6%) had B-lineage ALL, of which 85 (32.6%) were BCR-ABL-pos, 17 (6.5%) Ph-like (identified by FISH), 16 (6.1%) hypoploidy/near triploidy (Hy/Tri), and 67 (25.7%) pre-B ALL NOS. The remaining 48 (18.4%) had T-ALL. 30 pts (11.5%) had sALL (i.e. prior chemo/radiotherapy for another malignancy). HyperCVAD was the most common 1st line regimen (68.2%). 243 (93.1%) pts achieved Complete Remission (CR1) after induction therapy, and 203 (77.8%) were in CR1 at the time of alloHCT. Blina was administered for MRD+ in 14 pts (5.4%), and for relapsed/refractory ALL (R/R) in 13 (27% of R/R pts), 7 of whom received Blina as initial therapy for R/R. Donors were matched unrelated in 149 (57.1%), matched related in 98 (37.5%), and haploidentical in 14 (5.4%). Peripheral blood (PB) grafts were used in 233 (89.3%). 103 (54.5%) were donor:recipient (D:R) sex-matched, and 86 D:R mismatched [47 (24.9%) M:F; and 39 (20.6%) F:M]. Myeloablative conditioning was used for the majority (78.5%) mostly with Cy/TBI (60.5%). Standard GVHD prophylaxis regimens were used. Outcomes Median follow-up after transplant was 22.4 months (0.5-135), and 51 (19.5%) had REL. The 1, 2 and 5-year survival rates were 71.9%, 64.9%, and 54.1%, respectively (Figure 1). Acute GVHD developed in 144 (55.2%) and chronic GVHD in 100 (38.3%). Ph-like ALL, Blina for MRD+, Blina for R/R, sALL and CD20-pos had no independent impact on OS. In contrast, age>60, Hy/Tri, and >CR1 at alloHCT were associated with worse OS in UVA, however, in MVA only pre-B ALL NOS was associated with better OS. Female:male D:R status was associated with inferior OS. Blina for R/R disease was associated with increased risk of REL in UVA [HR 5.26 95% CI (1.33, 20.00), p=0.017], whereas other novel high risk groups had no impact on REL. In contrast, T-ALL, Hy/Tri and >CR1 at AlloHCT were associated with increased REL in UVA, but only T-ALL and Hy/Tri continued to predict for increased REL in MVA. Secondary ALL was associated with increased NRM in UVA [HR 1.96 95% CI (1.07, 3.57), p=0.028], whereas other novel high risk groups had no impact on NRM. In contrast, age>60, >CR1 at AlloHCT and D:R sex mismatch were associated with higher NRM in UVA, but only sex mismatch and >CR1 at AlloHCT were associated with higher NRM in MVA. TBI use was associated with higher risk of acute GvHD (p=0.008) and ATG use with lower risk chronic GVHD (p<0.001). Similarly non-PB grafts were associated with a lower risk of chronic GVHD (p=0.005). Results for OS, REL, NRM, acute and chronic GVHD analysis are shown in Table 1. Conclusion Novel high risk groups (CD20+, Ph-like and sALL) do not appear to adversely impact OS after alloHCT, although sALL was associated with increased risk of NRM. Interestingly, pre-B-ALL NOS appear to be associated with favorable OS. Novel targeted therapies also do not independently predict outcome, with the exception of Blina for R/R ALL which may be associated with REL after subsequent alloHCT (a subgroup for whom novel maintenance strategies should be explored). Our analysis highlights the importance of allo-HCT for novel high risk ALL subgroups. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Foran:Agios: Honoraria, Research Funding.

Abstract Introduction Autologous stem cell transplantation (ASCT) plays a central role in the treatment of multiple myeloma (MM), even in the era of novel therapies (Gonsalves et al, 2018). Given the efficacy of the latter, as well as for logistical reasons, many patients opt to store their stem cells and delay ASCT until the time of progression. Delayed transplant does not appear to affect overall survival (OS) (Attal et al, 2017). However, in the "salvage" setting, the impact of treatment with additional chemotherapy prior to ASCT is unknown. One study, albeit in the front-line, suggested that in patients achieving less than a partial response (PR), additional induction prior to ASCT did not improve survival (Vij et al, 2015). The present study investigates the role of induction therapy prior to salvage ASCT. Methods We identified 380 patients who underwent ASCT >12 months after being diagnosed with MM from January 1, 2006 to July 1, 2017 at Mayo Clinic Rochester. 121 had a delayed ASCT, but no International Myeloma Working Group (IMWG) progression prior to ASCT and were excluded. Another 17 patients achieved less than PR prior to ASCT, thus were deemed primary refractory and excluded. Finally, 8 patients were excluded because they received a planned tandem ASCT. Thus, 234 patients were included in the present study, which was approved by the Mayo Clinic Institutional Review Board, in accordance with the Declaration of Helsinki. We refer to the time of progression prior to ASCT, after which we examined the use of pre-ASCT therapy, as T0 to avoid confusion. Time to next therapy (TNT) was defined as the time from ASCT (stem cell infusion, Day +0) to the initiation of a new therapy, not including planned consolidation or maintenance. Patients who were alive and had not received any new therapies, or died before receiving another therapy were censored at the time of last follow up, as of May 15, 2018. OS was defined as the time from Day +0 to death from any cause, with living patients censored at the time of last follow-up. TNT and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was used for univariate and multivariate analysis. High-risk cytogenetics were defined as del(17/17p), t(4;14), t(14;16), and t(14;20). The Mann-Whitney U test and Fisher's Exact test were used to compare continuous and categorical variables, respectively. Statistical analysis was completed using JMP 13.0 (SAS Institute Inc., Cary, NC, USA). Results Of the 234 patients who underwent salvage ASCT, 188 were treated with additional chemotherapy after T0 (hereafter referred to as "pre-ASCT induction"), whereas 46 patients went directly to ASCT. Baseline characteristics were comparable, however more patients in the pre-ASCT induction group had >1 progression prior to ASCT (28% vs. 9%, p= .0065) and had a trend towards a shorter duration of response (DOR) prior to T0 (14.7 vs. 18.5 months, p= .12). Intuitively, the pre-ASCT induction group had a longer time from T0 to ASCT (5.3 vs. 2.3 months, p< .0001). The median TNT for the entire cohort of 234 patients from Day +0 was 17.2 months (95% CI, 14.8-19.7); median OS was 50.4 months (95% CI, 43.3-60.7). TNT and OS were comparable between the two treatment groups (Figure 1). After adjusting for other significant prognostic factors, such as DOR prior to T0 and the presence of high risk cytogenetics, treatment with pre-ASCT induction did not significantly affect TNT or OS (Table 1). However, among the 188 patients treated with pre-ASCT induction, the subsequent depth of response prior to ASCT significantly affected TNT (Figure 2A) and OS (Figure 2B). TNT at 1-year post ASCT was 79.2% for patients achieving a ≥VGPR, 62.1% in those who achieved a PR or stable disease, and 45.7% for patients who had relapsed/refractory MM at the time of ASCT or received >2 lines of pre-ASCT therapy (p= .0003). Interestingly, the time from diagnosis to T0 was comparable between these 3 groups (27 vs. 28 vs. 26 months, respectively, p= .26). Conclusions Many patients with MM do not undergo ASCT until disease progression. In our cohort of 234 patients who underwent salvage ASCT, outcomes were similar whether patients received pre-ASCT induction or not. However, among the 188 patients treated with pre-ASCT induction, deeper responses correlated with significantly longer TNT and OS after ASCT. Further research into the role of chemotherapy prior to delayed ASCT in the era of novel agents is warranted. Disclosures Gertz: annexon: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Teva: Consultancy; janssen: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Celgene: 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; KITE: 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.