Median Duration Of CR Research Articles

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

1082MO 5-year characterization of complete responses in patients with advanced melanoma who received nivolumab plus ipilimumab (NIVO+IPI) or NIVO alone

5-year outcomes of patients (pts) with a CR to NIVO+IPI or NIVO alone and factors associated with continued CR or relapse are unknown. The current pooled analysis addresses these key questions, including a 12-mo CR landmark analysis used to decrease the time guarantee bias. In this post hoc analysis, 5-yr data were pooled from the phase III CheckMate 066 and 067 studies and the phase II CheckMate 069 study of pts with treatment-naive, advanced melanoma. Analyzed pts received either the approved regimen of NIVO+IPI followed by NIVO monotherapy or NIVO monotherapy. Characteristics and outcomes of pts with a CR (by RECIST) were investigated, including 12-mo landmark survival analyses to determine the likelihood of being alive at 5-y among pts in CR by 12 mo (to mitigate the time guarantee bias). Minimum follow-up was 60 mo since randomization of the last pt in each study; pooled median mo of follow-up was 63 for NIVO+IPI (n=409) and 64 for NIVO (n=526). CRs were demonstrated in 96 (23%) NIVO+IPI pts and 102 (19%) NIVO pts; of CR pts alive at 5 yrs, 75/79 (95%) and 85/91 (93%) had not received subsequent systemic therapy. Baseline characteristics significantly associated with CR (Table) were M stage (NIVO+IPI), PD-L1 ≥ 5% (NIVO), normal lactate dehydrogenase (LDH; both) and fewer disease sites (both). Median duration of CR and median time to subsequent systemic therapy were not reached in either group. Median mo (Q1, Q3) to CR was 9.1 (2.8, 23.1) for NIVO+IPI and 11.8 (5.8, 26.5) for NIVO alone. In pts in CR at 12-mo, 5-y OS for NIVO+IPI and NIVO respectively was 85% and 86%; PFS was 84% and 82%. NIVO+IPI- or NIVO-treated pts in CR at 12 mo have a high likelihood of being alive at 5 y even without subsequent systemic therapy. Several baseline pt characteristics were associated with CR duration. Factors associated with CR may differ for NIVO+IPI and NIVO alone. Biomarker analyses are ongoing.Table: 1082MONIVO+IPINIVOn/NCR % (95% CI)P-valuen/NCR % (95% CI)P-valueLDH status >ULN ≤ULN16/138 80/26912 (7-18) 30 (24-36)<0.000119/191 81/31710 (6-15) 26 (21-31)<0.0001LDH status > 2xULN ≤ 2xULN2/43 94/3645 (1-16) 26 (21-31)0.00202/58 98/4503 (<1-12) 22 (18-26)0.0010M stage M0 M1A M1B M1C9/19 20/62 30/98 37/22947 (24-71) 32 (21-45) 31 (22-41) 16 (12-22)0.00048/35 15/70 30/110 49/31123 (10-40) 21 (12-33) 27 (19-37) 16 (12-20)0.0587No. lesion sites 1 2-3 >353/128 36/211 7/7041 (33-50) 17 (12-23) 10 (4-20)<0.000140/130 50/303 12/9131 (23-40) 16 (12-21) 13 (7-22)0.0007PD-L1 ≥5% <5%20/92 64/26622 (14-32) 24 (19-30)0.650742/139 58/33530 (23-39) 17 (13-22)0.0017ULN, upper limit of normal. Open table in a new tab

The Choice of Treatment for Elderly AML-Patients: 7+3 or Low Doses ARA-C

Background Acute myeloid leukemia (AML) in older adults is a biologically and clinically distinct entity. These patients often have comorbidities, and their treatment must be chosen with caution. In AML patients over 60y old, cure rates are under 10% even after intensive chemotherapy (CT). Aim To compare the efficacy of different therapeutic approaches in elderly AML-pts treated in NRCH. Methods From 2002 till 2019, NRCH has conducted a prospective non-randomized study which included 80 AML-patients 60-81y (Me - 67y): 60-65 yy (n=53) and &gt;65y (n=27); M/F - 35/45; de novo AML n=61 (76,25%), AML from MDS - n=13 (16,25%), «secondary» AML - n=6 (7,5%); cytogenetic risk: favorable n=1 (1,25%), intermediate n=49 (61,25%), poor n=30 (37,5%). The patients were stratified to different treatment approaches according to age. Patients 60-70y (n=40) mostly received 1-2 induction cycles 7+3 (ARA-C 100 mg/m2 bid; Dauno - 45-60 mg/m2 ), then 2 consolidation cycles 7+3 (Dauno - 45 mg/m2) and 2 years maintenance (5+5 with 6-MP). Patients &gt;70y (n=22) were usually treated with 1-2 induction and 2 consolidation cycles of low dose Ara-C (LDAC) (10 mg/m2 sc bid, 28-days) and 3 years maintenance with 21-28-days LDAC. In some cases, fit patients over the age of 70y have got 7+3 (n=5) and some younger with comorbidities - LDAC (n=13). The analysis was done in May 2019. We evaluated treatment outcome according to age, cytogenetics and type of CT. Results The CR rate in the whole group of elderly AML-pts was 57,5% (46/80) with a median CR-duration - 10 mon (1-138 mon), early death - 16,25% (13/80) and resistance - 26,25% (21/80) with no major differences in the two age cohorts (&lt;&gt;70y). In order to assess of the efficacy of two chemotherapy options we have compared 7+3 and LDAC in patients aged 60-65 and older. In patients aged 60-65 CR-rate was higher -75% (21/28) after 7+3 vs 50% (2/4) after LDAC, with less resistant forms - 7% (2/28) vs 25% (1/4), respectively. In &gt; 65y group CR-rate was identical in pts after 7+3 (47%, 8/17) and after LDAC (55%, 17/31) with similar numbers of resistant forms: 41% vs 29%. Early death rate did not differ among the groups. There was statistically higher CR-rate and lower resistant forms on 7+3 in pts aged 60-65 compared to older pts. - 75% vs 47% (p&lt;0.05) and 7% vs 41% (&lt;0.005) (Tab.1). Long-term results in the whole cohort of elderly patients were as follows: 1-y OS - 46%, DFS - 52,2%, 5-y ОS - 13%, DFS - 9% with high relapse rate (70%) development, mostly with early occurrence (Me - 12.8 mon). The median survival was statistically longer in patients aged 60-65y (n=32) comparing to older ones (n=48) - 15.4 vs 8 mon, respectively (p=0.0542), but DFS was equal (Fig.1). Higher incidence (87% vs 74%) and earlier relapse development (12 vs 16 mon) were registered in the group with poor cytogenetics comparing to favorable/intermediate (p=0,022). We didn't observe significant difference in long-term outcome of AML-pts older or younger 70y. Standard LDAC duration is 10-14 days, twice less than we used in our study. A landmark-analysis (from day 30 of induction) has shown that, if the 1st course-duration was less than 28 days, the median survival was shorter - 5,9 mo in comparison with 14,9 mo in pts with 28-days LDAC (p=0.12). The efficacy of 28-days LDAC was very similar to 7+3, mainly in patients aged 66 and older (Fig.2). Conclusion The outcome in elderly AML-patients is determined by age (more or less 65y) and the group of cytogenetic prognosis (poor vs favorable/intermediate). Intensive induction (7+3) is more preferable in patients aged 60-65 y as it produced the higher CR-rate and less resistant forms, results that are comparable to younger AML-patients. In patients older than 65y - CR-rate after 7+3 or 28-day LDAC was identical, and 28-days LDAC may become the choice of treatment for patients older than 65y. However long-term results are generally poor so new therapeutic strategies for elderly AML-patients are highly needed. Disclosures No relevant conflicts of interest to declare.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Commonly Presents in the Setting of Prior or Concomitant Hematologic Malignancies (PCHM): Patient Characteristics and Outcomes in the Rapidly Evolving Modern Targeted Therapy Era

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Commonly Presents in the Setting of Prior or Concomitant Hematologic Malignancies (PCHM): Patient Characteristics and Outcomes in the Rapidly Evolving Modern Targeted Therapy Era

916P - Health-related quality of life (HRQoL) and updated follow-up from KEYNOTE-057: Phase II study of pembrolizumab (pembro) for patients (pts) with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG)

916P - Health-related quality of life (HRQoL) and updated follow-up from KEYNOTE-057: Phase II study of pembrolizumab (pembro) for patients (pts) with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG)

S875 SUBCUTANEOUS DARATUMUMAB + CYCLOPHOSPHAMIDE, BORTEZOMIB, AND DEXAMETHASONE (CYBORD) IN PATIENTS WITH NEWLY DIAGNOSED AMYLOID LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED SAFETY RUN‐IN RESULTS OF ANDROMEDA

Background:The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab‐based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis.Aims:We present the 1‐year follow up on safety and efficacy data for the 28 patients enrolled in the safety run‐in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis.Methods:Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT‐ProBNP ≤8,500 ng/L. In the safety run‐in, patients received DARA (1,800 mg in 15 mL) co‐formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter.Results:Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow‐up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (&gt;6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow‐up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1.Summary/Conclusion:DARA‐CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well‐tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

S876 GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-MUTATED (FLT3MUT+) RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PHASE 3 ADMIRAL TRIAL

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab-based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1-year follow up on safety and efficacy data for the 28 patients enrolled in the safety run-in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, patients received DARA (1,800 mg in 15 mL) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow-up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow-up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA-CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well-tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

PS961 PATIENTS WITH RELAPSED MIXED PHENOTYPE ACUTE LEUKEMIA HAVE SHORT REMISSION DURATION WITH RE‐INDUCTION: A SINGLE CENTER EXPERIENCE

Background:Mixed phenotype acute leukemia (MPAL) is a heterogeneous disease consisting of acute leukemias expressing markers of both myeloid and lymphoid lineages. It is associated with a poor prognosis with a median overall survival of 11 months. There is no consensus regarding treatment at diagnosis or at relapse.Aims:To study the outcomes and characteristics of relapsed MPAL and identify prognostic featuresMethods:Patients aged 18 years or older meeting the criteria for MPAL according to the WHO 2016 classification in Princess Margaret Cancer Center between January 1, 2000 and December 31, 2018 were studied. Patients receiving curative intent therapy were assessed for response. The Wilcoxon‐Mann‐Whitney test for continuous variables and the Chi‐squared test for categorical variables were used.Results:Among the 59 MPAL patients included in this study, 42 (71%) received induction chemotherapy. Of those, 32 (76%) received ALL type treatment and 10 (24%) received AML type treatment. Tyrosine kinase Inhibitors were given to all patients who had Ph+ disease. Complete remission (CR) to ALL treatment was achieved in 26 (81%) out of 32 and 6 (50%) of the 12 patients treated with AML therapy. Eighteen (56%) of the patients relapsed with a median CR1 duration was 13.1 months. We further evaluated this group of 18 relapsed patients to identify risk factors for relapse.One patient had isolated CNS relapse. The immunophenotype was identical to the diagnostic type for seven patients (38%). Lineage switch occurred in 9 (56%) patients. The lineage switch correlated with the treatment type with 4 (44%) patients who received ALL‐type therapy switching to AML (Table 1).Diagnostic karyotype was reviewed for 18 patients with relapse. 16 (94%) were abnormal and classified as: complex (43%), monosomy 7 (43%), t(9;22)(q32;q11) (5%) and KMT2A rearranged (5%). There were four patients in whom karyotype was available both at the time of diagnosis and at relapse. Two (50%) had the same cytogenetic abnormality at both time points and one showed clonal evolution with an acquisition of monosomy 7.CR2 was achieved in 4 (44%) of the 9 patients that were re‐induced and the median duration was only 4.2 months. Of the 3 (75%) patients that relapsed after re‐induction, 1 patient switched lineage to blastic plasmocytoid dentritic leukemia. One patient remains in a CR2 after receiving blinatumumb with a follow up of 5 years.imageClinical outcome data was compared between the relapsed MPAL group and the non‐relapsed MPAL group (n = 14). Males were more likely to relapse (p = 0.0209). Patients treated with ALL‐ targeted treatment were less likely to relapse than those treated with AML‐targeted treatment (p = 0.03). There was an increased number of patients in the relapsed group who were KMT2a rearranged and this approached significance (p = 0.0517). However, there was no statistical difference in relapse when accounting for age, white cell count, MPAL classification and other cytogenetic abnormalities.Median survival after relapse was 7.6 months (range 1–72 months). Overall survival (OS) at 3 years was 5% for the relapsed patients compared to 55% of the non‐relapsed patients (Figure 1). There was no difference in OS in patients who switched lineage.Summary/Conclusion:This is the first report on relapsed MPAL and our findings highlights the dismal overall survival but does suggest ALL‐treatment seems more effective with a higher response rate. Further studies into the genomic aspects of the disease are needed and prospective multicenter trials are required to further appreciate this not well understood disease.

PB1666 WHERE IS THE PLACE OF PET/CT IN DIAGNOSTIC IN PATIENTS WITH LYMPHOBLASTIC LYMPHOMA AND ACUTE LYMPHOBLASTIC LEUKEMIA WITH EXTRAMEDULLARY INVOLVEMENT?

Background:Positron emission tomography/computed tomography (PET/CT) is emerging as an essential diagnostic tool in characterizing suspicious neoplastic lesions and staging malignant diseases. Most studies regarding the possible role of FDG‐PET/CT in the management of acute lymphoblastic leukemia (ALL) patients are very limited. But one can suggest the high role of PET/CT in the assessment of residual lesions after chemotherapy in patients with lymphoblastic lymphoma (LBL) and ALL with extramedullary involvements.Aims:The aim of the study was to estimate the ability to accumulate 18F‐FDG radiopharmaceuticals by tumor cells in PET/CT in patients with ALL/LBL and assess the prognostic value of the PET/CT after the consolidation therapy (with or without autologous stem cell transplantation (autoSCT)) in patients with Ph‐negative ALL/LBL who received therapy according to the protocols of the Russian research group ALL‐2009/ALL‐2016.Methods:PET/CT was performed in 3 patients with different types of newly diagnosed ALL before the start of the therapy and after the end of induction. Characteristic of patients were: the first‐ male, 55 age, with BII type Ph‐negative ALL, with t(6;11) with generalized bone involvement and ossalgia; the second ‐ female, 33 age, with BII type Ph‐positive ALL, p190type of transcript without extramedullary involvement; and the third‐ female, 28 age, with TIII type ALL, with TCR A/D rearrangement, with massive mediastinal lesion, bilateral renal and ovarium involvement.PET/CT was applied in 10 patients with Ph‐negative ALL/LBL after the end of consolidation by ALL‐2009/ALL‐2016 protocols. The characterization of patients (Table): 6/4 (60%/40%) M/F, 9/1 (90%/10%) B/T type Ph‐negative ALL, 8/1/1 (80%/10%/10%) with mediastinum/lymph nodes/renal and ovarium involvements, 3/7 (30%/70%) with or without bone marrow involvement, nobody with CNS involvement, 5/5 (50%/50%) with or without autoSCT, 3/7 (30%/70%) with or without radiotherapy in consolidation.Results:The results of PET/CT in three patients with different variants of newly diagnosed ALL/LBL were analyzed and it was shown that all patients had metabolic activity of 18F‐FDG in all morphologically and immunohistochemically (immunophenotypically) confirmed lesions (SUV 3,9‐8,7).An analysis of the results of PET/CT after the consolidation therapy with/without autoSCT in patients with Ph‐negative ALL was performed, and it has shown that all patients had PET‐negative remission of the disease and MRD negative status in bone marrow by flow cytometry. With a median follow‐up of 20.5 months (from 15 to 44 months), only one patient out of 10 patients had isolated CNS relapse after 10 months of remission. In another 9 patients, with a median CR duration of 19 months (from 14 to 43 months), complete clinical and hematological remission is maintained.Summary/Conclusion:The results demonstrated that all specific lesions in ALL/LBL patients, medullary and extramedullary, were capable to accumule 18F‐FDG in PET. This fact provides opportunities for further studies of this method in assessing the completeness of remission in patients with extramedullary lesions. The value of PET/CT in ALL/LBL patients with central nervous system involvement remained unexplored. If the suggestions arising from this report are confirmed, FDG‐PET/CT may be included in future clinical practice for disease staging, evaluating the response to the chemotherapy in identified lesions and in the restaging for recurrence of extramedullary disease.image

Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): Updated follow-up from KEYNOTE-057.

4530 Background: Upregulation of the PD-1 pathway has been observed in BCG-unresponsive NMIBC, suggesting that pembro may be beneficial. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study (NCT02625961); updated results for pts with carcinoma in situ (CIS) with or without papillary tumors (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary tumors who received adequate BCG therapy and were unable/refused to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts who developed HR NMIBC or progressive disease during treatment were required to discontinue. Key end points were complete response rate (CRR), duration of response, and safety. Results: 102 pts (median age, 73 years; CIS alone, 63.7%; median number of prior BCG instillations, 12) had enrolled in cohort A as of enrollment cutoff. Median (range) duration of follow-up was 15.8 mo (4.6-28.2) ; 3-mo CRR was 40.2% (95% CI, 30.6-50.4) by central assessment. Among 41 pts who had CR at 3 mo, median CR duration was 12.7 mo (range, 0+ to 20.5+ mo); 75.4% had a CR duration ≥ 6 mo; 52.6% had a CR duration ≥12 mo (Kaplan-Meier method); 24 pts (58.5%) maintained CR at last follow-up, and 15 (36.6%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle-invasive or metastatic disease. CRR was 44.6% for pts with CIS alone (n = 65), 41.7% for CIS with T1 tumors (n = 12), and 28.0% for CIS with high-grade Ta tumors (n = 25). Treatment-related adverse events (AEs) occurred in 66 (64.7%) pts; most frequent (≥10%) were pruritus (10.8%), diarrhea (10.8%), and fatigue (9.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.7%) pts. Immune-mediated AEs occurred in 19 (18.6%) pts. Conclusions: Pembro continued to show encouraging antitumor activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial information: NCT02625961.

Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).

350 Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.

Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Longer-Term Follow-up Demonstrates Poor Outcomes in Patients with Skin-Only Presentation

Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Longer-Term Follow-up Demonstrates Poor Outcomes in Patients with Skin-Only Presentation

Genomics Reveal Potential Biomarkers of Response to Pembrolizumab after High Dose Cytarabine in an Ongoing Phase II Trial in Relapsed/Refractory AML

Background: Outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Programmed Death-1 (PD-1), an inhibitory receptor on T and B cells, suppresses immune activation. We hypothesized that administration of pembrolizumab, a monoclonal antibody targeting PD-1, after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML.Methods: We are conducting a multicenter phase II study of HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; ≥60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 in R/R AML pts 18-70 years. The primary objective of this study is to estimate the overall complete remission (CR + CRi) rate. Overall responders can receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (SCT) is permissible before or after maintenance phase.Results: To date, 26 pts are evaluable for safety and response (Table 1). Grade ≥3 immune-related adverse events have been rare and self-limiting. The overall CR rate is 35%. Of the 9 CR pts, 5 (56%) had no evidence of minimal residual disease (MRD) by standard monitoring. Notably, 2/3 primary refractory pts with inv(3) cytogenetics achieved CR and underwent SCT. Additionally, 1 pt with relapsed AML with most recent treatment refractory to HiDAC salvage achieved CR with no evidence of MRD. Five pts received maintenance pembrolizumab: 3 relapsed (median duration of CR = 2.8 months; range: 2-5.7 months), 1 proceeded to SCT after 2 cycles, and 1 initially achieved a partial remission (PR) and had stable disease for 12 cycles of maintenance pembrolizumab before progressing. Four pts received a SCT in CR (n=3) and morphologic leukemia free state (MLFS) (n=1). Grade II acute graft-versus host disease (GVHD) and moderate chronic GVHD was seen in 2/4 (50%) pts, respectively. With a median follow up of 10.8 months to date, median overall survival is 10.5 months (range: 1.8-20.8 months).We performed B cell receptor amplicon sequencing, T cell receptor (TCR) amplicon sequencing from CD8+ T cells, and RNA-seq from enriched blasts and non-blast fractions in bone marrow (BM) from 3 CR and 3 non-responders (NR) prior to HiDAC. From the BM blast enriched fraction, expression of innate immune genes such as NLRP12, C3, S100A9, S100A12 and CD14 correlated with response. Gene Set Enrichment Analysis (GSEA) demonstrated that CR correlated with expression of genes in the Toll Pathway, Lysosome pathway, and adaptive immune system while NRs were associated with expression of the PAR1 and GATA3 pathways. From the non-blast BM population, CR correlated with expression of cell-cycle genes such as CCNE1, CCNB2, E2F2, KIF18B and CDKN3. Not surprisingly, GSEA revealed that expression of cell cycle pathways correlated with response. CR correlated with increased expression of B cell metagenes and the inverse IPRES signature in the non-blast BM fraction. As previously reported, there was a significant increase in peripheral blood (PB) TCR diversity in CR pts. CR was also significantly associated with the abundance and richness of the non-blast BM fraction of the B cell heavy and both light chains suggesting that a broader immune response at baseline may be critical for response to HiDAC and pembrolizumab. Finally, CR correlated with increased expression of CD300E, CCR7, CCR4, CCR8 and CCL7 in PB CD8+ T cells suggesting that migration of monocytes, T and B cells is associated with response.Conclusions: Our findings demonstrate that pembrolizumab is well tolerated after HiDAC in an ongoing study in R/R AML. An encouraging response rate has been seen in a high-risk patient population without apparent additive toxicity post-SCT. Our RNA-seq and amplicon sequencing data indicate that biomarkers of response are present prior to therapy. Increased expression of innate immune genes expressed by leukemic blasts and cell cycle genes by the non-blast fraction correlated with response to therapy. Additionally, CR was associated with increased measures of B and T cell diversity and immune cell migration. Further immunogenomic biomarker correlates are ongoing to determine predictors of response to pembrolizumab after HiDAC in R/R AML. [Display omitted] DisclosuresZeidner:Tolero: Honoraria, Other: Travel Fees, Research Funding; Asystbio Laboratories: Consultancy; Merck: Research Funding; Takeda: Other: Travel fees, Research Funding; Rafael Pharmaceuticals: Other: Travel Fees; Celgene: Honoraria. Vincent:Merck: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Coombs:Incyte: Other: Travel fees; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Serody:Merck: Research Funding.

Potential Predictors of Induction Failure and Complete Remission Duration in FLT3-ITD Mutated Acute Myeloid Leukemia

Potential Predictors of Induction Failure and Complete Remission Duration in FLT3-ITD Mutated Acute Myeloid Leukemia

Use of Gemtuzumab Ozogamicin for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (AML) or Acute Promyelocytic Leukemia (APL) in an Expanded Access Setting at Our Cancer Consortium

Use of Gemtuzumab Ozogamicin for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (AML) or Acute Promyelocytic Leukemia (APL) in an Expanded Access Setting at Our Cancer Consortium

Pre-Transplant Monocytic Myeloid-Derived Suppressor Cell Frequency Has No Prognostic Role for Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Remission

INTRODUCTION: Emerging data indicate myeloid-derived suppressor cells (MDSCs) adversely impact outcomes of patients with a variety of malignancies. However, it is less clear how MDSCs affect acute myeloid leukemia (AML) disease biology or the response of AML patients to treatment. Here, we studied a cohort of people with AML undergoing hematopoietic cell transplantation (HCT) in first complete remission (CR1) to examine the relationship between the monocytic subtype of MDSCs (M-MDSCs), pre-transplant measurable residual disease (MRD) status, and outcome after HCT.PATIENTS AND METHODS: Adults ≥18 years of age were included if they underwent first allogeneic HCT with myeloablative or nonmyeloablative conditioning for AML in CR1 from April 2006 until October 2014. Prospective MRD testing in bone marrow aspirates was performed routinely via 10-color multiparameter flow cytometry (MFC) as part of the pre-transplant work-up. Pre-transplant MFC data were used retrospectively to quantify M-MDSCs as the proportion of monocytes (identified by side scatter properties and CD14 positivity) with low or negative expression of HLA-DR. M-MDSC frequency was then expressed as a percentage of the total number of viable cells in the sample. Available combinations of antigens measured by MFC did not allow for the identification of other MDSC subsets (e.g. granulocytic MDSCs).RESULTS: We identified 349 adults undergoing allogeneic HCT for AML in CR1 for whom pre-transplant MRD testing was performed and for whom follow-up data were available. Of these, 8 had to be excluded because of insufficient MFC events available for identification of M-MDSCs. In the remaining 341 patients, M-MDSC frequency ranged from <0.001% to 6.53%, with a median of 0.18% (25th percentile: 0.06%; 75th percentile: 0.40%). Patients with lower (i.e. <median) frequency of M-MDSCs were less likely male (p=0.01) and more likely had recovered neutrophil and platelet counts (p=0.001) than patients with higher (i.e. ≥median) frequency of M-MDSCs. There was no difference with regard to all other examined characteristics (age, WBC and cytogenetic risk at diagnosis, type of AML, median CR duration before HCT, donor type, and conditioning intensity). The proportion of MRD positive (“MRDpos”) patients was similar between those with lower vs. higher M-MDSC frequency (18.8 vs. 24.6%, p=0.20). Moreover, while MRD negative (“MRDneg”) patients (n=267) differed statistically significantly from MRDpos patients (n=74) with regard to several characteristics such as more favorable disease risk and lower proportion of secondary AML, there was only a statistically non-significant trend toward lower M-MDSC frequency in MRDneg patients (0.16% [range <0.001-5.61%] vs. 0.22% [range <0.001-6.53%], p=0.09).The median follow-up time after HCT among all survivors was 5.8 (range, 2.0-11.4) years. The time was slightly longer for survivors with lower compared to those with higher M-MDSC frequency (6.1 [range 2.6-11.4] vs. 5.1 [range 2.0-11.3] years; p=0.0076). Stratified by the median M-MDSC frequency, the 3-year estimates of overall survival were similar for patients with lower and higher pre-HCT M-MDSCs (58.2% [95% confidence interval 50.4-65.2%] vs. 57.6% [49.8-64.7%]), as were 3-year estimates for relapse free survival (53.5% [45.7-60.7%] vs. 48.3% [40.6-55.6%]), 3-year estimates of the cumulative incidence of relapse (31.8% [24.9-38.8%] vs. 34.6% [27.6-41.8%]), and 3-year estimates of non-relapse mortality (14.7% [9.9-20.5%] vs. 17.0% [11.8-23.0%]). Analyses restricted to the subset of patients undergoing myeloablative (MA) conditioning or those undergoing MA conditioning in MRDneg remission showed qualitatively similar results.CONCLUSIONS: In the largest study to date examining the role of M-MDSCs in AML, we found no convincing evidence for a prognostic role of these cells for adults undergoing allografting in CR1. DisclosuresWalter:Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy.

Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): Results of a phase 1 study.

7000 Background: IVO is an oral, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is being evaluated in a phase 1 dose escalation and expansion study of mIDH1 advanced hematologic malignancies (NCT02074839). Here we report updated efficacy and safety data from all patients with R/R AML receiving IVO 500 mg once daily (QD). Methods: The primary efficacy endpoint was the CR+CRh rate (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]). CRh was defined as absolute neutrophil count > 0.5 × 109/L and platelet count > 50 × 109/L. The overall response rate (ORR) comprised CR, CR with incomplete hematologic or platelet recovery, partial response, and morphologic leukemia-free state. The data cutoff date for this analysis was Nov 10, 2017. Results: A total of 258 patients were treated with IVO. Among 179 R/R AML patients who received IVO 500 mg QD, 17 (9.5%) remained on treatment at data cutoff. In R/R AML patients, the CR+CRh rate was 31.8% (95% CI: 25.1%, 39.2%), including CR in 24.0% (95% CI: 18.0%, 31.0%). Median duration of CR+CRh was 8.2 months (95% CI: 5.6, 12.0), and median duration of CR was 10.1 months (95% CI: 6.5, 22.2). The ORR was 41.9% (95% CI: 34.6%, 49.5%). Treatment was well tolerated; the most common adverse events (AEs) of any grade, irrespective of causality and occurring in ≥25% of 179 R/R AML patients were diarrhea (33.5%), leukocytosis (31.3%), nausea (31.3%), febrile neutropenia (29.1%), fatigue (28.5%), and electrocardiogram QT prolonged (25.7%). The majority of these AEs were grades 1–2 and unrelated to treatment. IDH differentiation syndrome (IDH-DS) was reported in 19 of 179 (10.6%) patients, including grade ≥3 IDH-DS in 9 (5.0%); study drug was held owing to IDH-DS in 6 patients (3.4%), and no instances of IDH-DS led to dose reduction, permanent treatment discontinuation, or death. Updated mutation clearance results will be provided. Conclusions: In a high-risk, molecularly defined R/R AML patient population, IVO induced durable remissions and was well tolerated. Studies in previously untreated AML populations are ongoing. Clinical trial information: NCT02074839.

Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.

Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Long-Term Outcomes of Patients with Acute Myeloid Leukemia Treated with Salvage High-Dose Etoposide and Cyclophosphamide

BackgroundSalvage chemotherapy using high-dose etoposide and cyclophosphamide (VP-Cy) was developed for acute leukemia and myeloid malignancies resistant to cytarabine-based induction regimens. The Leukemia/Bone Marrow Transplant (L/BMT) program of British Columbia has a 25-year experience using VP-Cy for patients with relapsed and refractory (R/R) acute myeloid leukemia (AML). We report on a retrospective analysis to evaluate the efficacy and early toxicity of this regimen.MethodsThe L/BMT database was searched to identify R/R AML patients treated with VP-Cy. Patients were treated with etoposide 2.4 g/m2 given as continuous infusion over 34 hours on days 1-2 followed by cyclophosphamide 2 g/m2/day on days 3-5. The primary aims of this analysis were to determine response rate, long-term survival outcomes, and early toxicity. Secondary aims were to determine the impact of initial induction chemotherapy, using either standard-dose cytarabine and daunorubicin (7+3) or high-dose cytarabine and daunorubicin (HiDAC-D), on response rate to salvage as well as to assess the impact of cytogenetics and FLT3-ITD mutations on outcome. Survival curves were calculated using the Kaplan-Meier method, and comparisons between curves were made using the log-rank test. Chi-squared test was used to compare differences in categorical variables.Results169 patients diagnosed with R/R AML treated with VP-Cy from 1991-2015 were identified. Baseline characteristics are shown in Table 1. CR rate was 45% and 5-year OS was 20% (95% CI 14-26%) for the entire cohort. Rate of CR (p=0.98) and median OS (p=0.8) were not different between cohorts receiving standard-dose cytarabine vs. high-dose cytarabine during initial induction. 74% (56/76) of responding patients received allogeneic hematopoietic stem cell transplant. 42% (32/76) of patients relapsed after initially responding to VP-Cy and the median CR duration was 221 days (range: 36 to 2561 days). In responding patients (n=76), 5-year relapse-free survival (RFS) and OS were 33% (95% CI 24-46%) and 35% (95% CI 25-47%) respectively. Initial disease status did not significantly influence response rate [52% (refractory day 14) vs. 42% (refractory day 28) vs. 47% (relapsed), p=0.46] although median OS was longer in patients with refractory disease [422 days (refractory day 14) vs. 281 days (refractory day 28) vs. 122 days (relapsed), p=0.03)]. Patients with FLT3-ITD mutation (30/78) had lower CR rate (23% vs. 53%; p=0.01) and worse OS (median OS 135 days vs. 357 days; p<0.0001) compared to those without. Patients with adverse risk cytogenetics (34/169) had a trend towards lower CR rate (38% vs. 50%; p=0.2) and a significantly worse OS (median OS 155 days vs. 304 days; p<0.0001) compared to patients with favourable/intermediate cytogenetics. Rate of early death (<60 days) was 12% (20/171) and causes included: bacterial infection (n=4), fungal infection (n=3), intracranial hemorrhage (n=1), and progressive AML (n=9).ConclusionVP-Cy is an effective salvage regimen with response rates, long-term survival and rates of early death comparable to reported outcomes using cytarabine-based salvage regimens. Initial dose of cytarabine given during induction did not influence response rate or survival. The probability of long-term survival for the entire cohort was low (20%) and outcomes were significantly worse in patients with FLT3-ITD mutation and adverse risk cytogenetics, emphasizing the need for investigation of novel treatments in these groups. [Display omitted] [Display omitted] [Display omitted] DisclosuresSong:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Otsuka: Honoraria. Toze:Roche Canada: Research Funding. Gerrie:Roche Canada: Research Funding.