Stem Cell Transplantation In First Remission Research Articles

A Randomized Comparison of Liposomal Daunorubicin/Daunorubicin Combined with Low-Dose Cytarabine and Etoposide or High-Dose Cytarabine and Fludarabine in Induction Treatment of Pediatric AML Using MRD-Based Risk Stratification in the NOPHO-DBH AML 2012 Protocol

Background: In pediatric acute myeloid leukemia (AML), measurable residual disease (MRD) by flow cytometry (FCM) after induction therapy has emerged as one of the strongest prognostic factors. We designed a phase III study (NOPHO-DBH AML2012) using an intensified response-guided induction with mainly MRD based risk stratification. All high-risk patients were treated with allogeneic stem cell transplantation (SCT). The study contained two randomized questions: 1) a randomized comparison of mitoxantrone and liposomal daunorubicin (DNX) in first induction which is reported elsewhere and 2) the comparison of AD(x)E (low dose cytarabine, DNX, etoposide) and FLAD(x) (fludarabine, high dose cytarabine, DNX [60 mg/m 2 x III]) which was proven effective in refractory/relapsed AML in the second induction course Patients and methods: The study was population-based and conducted in the Nordic countries, Belgium, Hong Kong and the Netherlands (NOPHO-DBH collaboration). Between March 2013 and November 2017, 194 were randomized 1:1 to AD(x)E or FLAD(x). At this time DNX became unavailable and randomization was paused. After almost 18 months, when it became clear that the shortage was permanent, randomization was resumed (February 2019-July 2021) but with daunorubicin substituting DNX. In total 306 patients were included (152 AD(x)E, 154 FLAD(x)). Randomization was stratified according to treatment arm and response to course 1. The primary endpoint was the proportion with MRD <0.1% after the second induction. Patients with MRD ≥ 0.1% after course 2 or MRD ≥ 15% after course 1 or with FLT3-ITD and NPM1 wild type were assigned high-risk (HR) and consolidated with SCT whereas standard-risk (SR) received 3 chemotherapy courses ( CBFB:: MYH11 2 courses) (Fig 1). Estimates of overall survival (OS) and event-free survival (EFS) from date of diagnosis and given at 5 years were calculated by the Kaplan-Meier method and given as percentage± standard error with differences tested by log rank test. Results: Patient and disease characteristics were similar between treatment arms (Table 1). For all 306 randomized patients EFS was 66.8±2.8% and OS 80.5±2.4%. 232 (76%) had SR with EFS of 71.1±3.1% and OS 86.9±2.3% whereas 56 (18%) had HR with EFS 67.5±6.3% and OS 70.1±6.3%. Median observation time for patients without events was 68 months. There was no difference in proportion of patients with MRD < 0.1% in the randomized groups with 112/152 (74%) for AD(x)E and 120/154 (78%) for FLAD(x). CR rates were 93.4% for AD(x)E and 96.1% for FLAD(x). Survival outcomes for AD(x)E and FLAD(x) were very similar with EFS 67.9±3.8 vs 65.9±3.9 ( P=.93) and OS 82.0±3.2 vs 79.1±3.4 ( P=.60) (fig 1). Univariate Cox regression on all factors in table 1 showed statistical significance for RUNX1:: RUNX1T1 associated with better EFS (Hazard ratio[HzR] 0.26 CI 0.10-0.70) and “other” aberrations with worse EFS (HzR 2.21 CI 1.49-3.27). For OS, both RUNX1:: RUNX1T1 (HzR 0.12 CI 0.02-0.84) and CBFB:: MYH11 (HzR 0.12 CI 0.02-0.88) showed better outcome while the group “other” aberrations had increased HzR (1.77 CI 1.03-3.0). In multivariable analysis, RUNX1:: RUNX1T1 and CBFB:: MYH11 were the only factors significantly associated with EFS and OS (lower HzR) . One patient in each arm died from toxicity after course 2. There was a trend for increased toxicity in patients treated with FLAD(x), with 134 grade 3 (CTCAE4.0) toxicities registered after course 2 compared to 103 for AD(x)E and 37 vs 27 grade 4 toxicities. Also, 18 patients in the FLAD(x) group required ICU treatment compared to 9 for AD(x)E. Conclusion. Risk stratification based on MRD FCM and response-guided induction as used in the NOPHO-DBH AML 2012 protocol resulted in one of the best cure rates reported in newly diagnosed pediatric AML. The stratification allowed 75% of patients to receive standard-risk treatment without SCT in primary therapy. Patient with suboptimal response (ie our HR group) benefitted from SCT in first remission. Perhaps surprisingly, given the efficacy in relapsed AML, FLAD(x) did not improve outcome compared to AD(x)E. Since toxicity was higher we have opted to retain ADE in the upcoming protocol.

Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia

Background Blinatumomab improves overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD). Blinatumomab also improves OS when added to standard chemotherapy, irrespective of MRD status, in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Inotuzumab ozogamicin (INO) improves OS in the relapsed/refractory setting, and we hypothesized that the addition of INO to hyper-CVAD plus blinatumomab would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods In this phase II study, pts age 14-59 with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C (which was also dose reduced to 500 mg/m2 of MTX and 1 g/m2 of Ara-C with this amendment) and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results As of June 2023, 75 pts have been treated (38 without INO and 37 with INO). Pt characteristics are shown in Table 1. The median age across both cohorts was 33 (range, 18-59). 36 pts (48%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 overexpression by flow and/or TP53 mutation). Sixteen pts were in complete remission (CR) at enrollment after 1-2 cycles of off-protocol therapy, 10 of whom were MRD-negative by 6-color flow cytometry. All 59 pts (100%) with active disease upon study entry achieved CR, with 50 pts (84%) achieving CR after the first cycle. MRD negativity by flow (sensitivity 10 -4) was achieved in 60 of 65 evaluable pts (92%), with 43 pts (66%) achieving flow MRD negativity after the first cycle. Two of the 5 patients who did not achieve flow MRD negativity had NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have not yet received blinatumomab. Overall, 25 of 36 tested pts (69%) achieved next-generation sequencing-based MRD negativity at a sensitivity of 10 -6. The median duration of follow-up is 26 months (range, 1-77 months). Overall, 8 pts (11%) relapsed in the absence of SCT, 23 pts (31%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 3 pts (4%) died in CR, and 41 pts (55%) remain in continuous remission without SCT. Among the 10 relapses, 3 were in the CNS, 2 of which were CNS-only. All but one relapse occurred in pts with ≥1 poor-risk feature(s). Across both cohorts, the estimated 3-year OS was 88% and the 3-year relapse-free survival (RFS) was 79% . The 3-year OS rate for pts without a high-risk baseline feature was 93% vs 83% in pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 90% versus 87%). With a median follow-up of 18 months in the INO group, 3 pts (8%) have relapsed, 2 with CNS-only relapses, and none have died. The 18-month RFS in the cohorts with and without INO were 92% vs 76% (p=0.18), and the OS was 100% vs 84% (p=0.04) ( Figure 1). One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

A phase II trial of ponatinib and blinatumomab in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).

e19013 Background: Ponatinib and blinatumomab are both active in Ph+ ALL. A combination of these agents may lead to durable remissions when given in the frontline setting and may eliminate the need for chemotherapy or stem cell transplant (SCT). Methods: In this phase II study, patients (pts) with newly diagnosed Ph+ ALL received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for at least 5 years. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Pts also received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2023, 54 pts were with newly diagnosed Ph+ ALL were treated. Baseline characteristics are shown in the table. Among 35 pts evaluable for hematologic response, 23 (97%) achieved CR/CRi; 1 pt had early death. Among 48 pts evaluable for molecular response, 34 (71%) achieved CMR after 1 cycle, and 43 (90%) achieved CMR at any time. After 2 weeks of therapy, 18/35 tested pts (51%) achieved CMR in the peripheral blood. 34/38 tested pts (89%) achieved MRD negativity by next-generation sequencing at a level of 10-6. Four of these pts who were MRD-negative by NGS had detectable low-level BCR:ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). The median follow-up is 16 months (range, 1-55 months). Three patients relapsed after a median of 9 months of remission (range, 8-23 months), 1 in bone marrow with new E225V mutation and 2 extramedullary-only. Three pts have died (1 from intracranial hemorrhage, 1 from post-procedural hemorrhage, and 1 from brain aneurysm). There have been no leukemia-related deaths, the estimated 2-year EFS and OS are both 90%. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently low-level BCR:ABL1 positivity. Among the 47 pts in ongoing remission without SCT, the median duration of response is 15 months. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab is safe and effective in newly diagnosed Ph+ ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for SCT. Clinical trial information: NCT03263572 . [Table: see text]

Frontline Management of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) represent only 10%-15% of all non-Hodgkin lymphoma but encompass a diverse group of diseases with over 30 different subtypes. As a result of both disease heterogeneity and rarity, therapeutic progress of PTCLs has lagged behind B-cell lymphomas with very few randomized controlled studies to guide management. The most common subtypes are the so-called nodal PTCLs: PTCL-not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL), and nodal T follicular helper cell lymphoma (TFHL) lymphoma, the latter of which includes angioimmunoblastic T-cell lymphoma. Anthracycline-based primary chemotherapy is still the mainstay of treatment for these common PTCL subtypes, but in recent years, we have moved into an era where more personalized therapy can be applied in some settings. Cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin CHP-BV is the first therapy in PTCL to show an overall survival benefit and represents a new standard for ALCL; however, there is less therapeutic certainty in other CD30-positive PTCLs. Recurrent mutations of epigenetic modifier genes typify TFHLs lymphomas, and collective studies demonstrate a heightened sensitivity to epigenetic therapies, leading to trials integrating these agents in the frontline setting. Molecular studies of PTCL-NOS have defined at least two subtypes, GATA3 and TBX21, the former having a poorer prognosis, but how this guides therapeutics remains unknown. Outside of ALCL, there is a growing debate as to whether trials should focus on adding a novel agent to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or whether combination novel therapies should be explored in the frontline therapy setting. Finally, the role of consolidative autologous stem-cell transplant in first remission remains an area of active debate.

Outcomes Are Similar After Allogeneic Hematopoietic Stem Cell Transplant for Newly Diagnosed Acute Myeloid Leukemia Patients who Received Venetoclax + Azacitidine Versus Intensive Chemotherapy

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC+SCT patients, it was not significantly predictive of relapse and survival in the ven/aza+SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age.

P355: MINI-HYPER-CVD PLUS INOTUZUMAB OZOGAMICIN, WITH OR WITHOUT BLINATUMOMAB, IN OLDER ADULTS WITH NEWLY DIAGNOSED B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: UPDATES FROM A PHASE II TRIAL

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (INO) improve the outcomes of patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). These drugs may allow for use of less chemotherapy and improve remission durations and overall survival (OS) in older pts with newly diagnosed B-ALL. Aims: To evaluate the combination of low-intensity chemotherapy and INO with or without Blina, in older pts with newly diagnosed B-ALL. Methods: Pts ≥60 years with newly diagnosed Philadelphia chromosome (Ph)-negative B-ALL were eligible to receive mini-hyper-CVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day (D) 3 of cycle 1 and 0.8-1.3mg/m2 on D3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. POMP maintenance was given for up to 3 years. Starting with pt #50, the protocol was amended and INO was administered in fractionated doses with each of the 4 cycles of hyper-CVD (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of cycle 1; 0.3 mg/m2 on D2 and 8 of cycles 2-4) followed by 4 cycles of blina. The cumulative doses of INO given before and after this amendment were 4.3 mg/m2 and 2.7 mg/m2, respectively. Maintenance was also amended to include 12 cycles of POMP and 4 cycles of blina (1 cycle of blina after every 3 cycles of POMP). Results: 80 pts have been treated with a median age of 68 years (range, 60-87); 30 pts (38%) were ≥70 years. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics are summarized below (Figure 1A). The overall response rate (ORR) among 74 evaluable pts was 99% (CR, n=66; CRi, n=7). MRD negativity by flow cytometry was achieved in 61/76 pts (80%) after 1 cycle and 74/79 pts (94%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 79 pts who achieved remission, 33 (42%) are still in ongoing remission without stem cell transplant (SCT), 31 (39%) died in remission, 11 (14%) relapsed without SCT, and 4 (5%) proceeded to SCT in first remission (1 of whom subsequently relapsed). Notably, 9 pts (11%) later developed MDS/AML, 7 of whom had a TP53 mutation. Overall, 6 pts (8%) developed VOD, 1 after allogeneic SCT. With a median follow-up of 55 months (range, 3-119), the 5-year continuous remission and OS rates were 76% and 47%, respectively (Figure 1B). Pts aged 60-69 years had better outcomes compared with pts ≥70 years (5-year OS rates: 59% vs 27%, respectively; P=0.04) and as did those without poor cytogenetics (i.e. complex, KMT2A-rearranged, low-hypodiploidy/near-triploidy) compared with poor cytogenetics (5-year OS rates: 54% and 25%, respectively; P=0.02). Deaths in remission were more frequent in pts ≥70 years compared with those 60-69 years (70% vs 35%; P=0.005). The 5-year OS rates for pts age 60-69 without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24), and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0% respectively (Figure 1C). Presence of a TP53 mutation did not significantly impact OS (P=0.22). Image:Summary/Conclusion: Reduced-intensity chemotherapy plus INO, with or without blina, resulted in an ORR of 99% and a 5-year OS rate of 47% in older pts with newly diagnosed Ph-negative B-ALL. Outcomes were particularly favorable in those 60-69 years of age without poor-risk cytogenetics. Pts ≥70 years were at a higher risk of death in remission. A chemotherapy-free approach, with INO plus blina only, is therefore now being explored in this population.

P371: HYPER-CVAD WITH SEQUENTIAL BLINATUMOMAB, WITH OR WITHOUT INOTUZUMAB OZOGAMICIN, IN ADULTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-NEGATIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Background: Blinatumomab and inotuzumab ozogamicin (INO) are highly effective in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL); blinatumomab is also the only approved therapy for eradication of persistent or recurrent measurable residual disease (MRD) after initial ALL therapy. We hypothesized that early incorporation of blinatumomab and INO in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. Aims: We evaluated the efficacy and safety of hyper-CVAD with sequential blinatumomab, with or without INO, in pts with newly diagnosed Ph-negative B-cell ALL. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results: As of February 2022, 58 pts have been treated (38 without INO and 20 with INO). Pt characteristics are summarized in Table 1. Median age was 34 years (range, 17-59 years). 13 pts were in CR at enrollment. Among 45 pts with active disease at study entry, 100% achieved CR, with 80% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 32/42 evaluable pts (76%) after 1 cycle and 55/58 evaluable pts (95%) overall. Two of the 3 pts who did not achieved MRD negativity were later found to have a NUP214::ABL1 fusion. The median duration of follow-up is 26 months (range, 3-61 months). Overall, 5 pts (9%) did not undergo stem cell transplant (SCT) and subsequently relapsed, 18 pts (34%) underwent SCT in first remission (including 2 additional pts who relapsed post-SCT), 2 pts (3%) died in CR, and 33 pts (57%) remain in continuous remission without SCT. All relapses occurred in pts with ≥1 poor-risk feature(s), and no relapses have occurred beyond 2 years from the start of treatment. For the entire cohort, the 3-year continuous remission and OS rates were 84% and 85%, respectively (Figure 1). No relapses or deaths have occurred in the INO group, and the estimated 1-year OS rate is 100%. Treatment was overall well-tolerated. One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed. Image:Summary/Conclusion: Hyper-CVAD with sequential blinatumomab, with or without INO, is highly effective as frontline treatment of Ph-negative B-cell ALL, with an overall MRD negativity rate of 95% and a 3-year OS rate of 85%. Early outcomes with the addition of INO to this regimen are encouraging, with no relapses or deaths observed to date.

A phase II trial of a chemotherapy-free combination of ponatinib and blinatumomab in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

7009 Background: Ponatinib and blinatumomab are highly active in Ph+ ALL. A chemotherapy-free combination of these agents may lead to durable remissions and reduce the need for stem cell transplant (SCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or CML in lymphoid blast phase (CML-LBP) received up to 5 cycles of blinatumomab. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years. All patients (pts) received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2022, 55 pts were treated (35 ND, 14 R/R and 6 CML-LBP). Baseline characteristics and responses are shown in Table. Among 23 pts with ND Ph+ ALL evaluable for response, 22 (96%) achieved CR/CRi; 1 pt had early death due to myelosuppression from prior chemotherapy. Among 13 evaluable pts with R/R Ph+ ALL, 12 (92%) achieved CR/CRi. The CMR rates for the ND, R/R and CML-LBP cohorts were 64%, 71%, and 17% after cycle 1 and were 85%, 79%, and 33% overall, respectively. In the ND cohort, 4/17 evaluable pts (24%) achieved CMR in the peripheral blood within 1 week, and 9/15 (60%) within 2 weeks. The median follow-up is 11 months (range, 1-46+ months). Among the 35 pts in the ND cohort, 33 pts (94%) are alive and in continuous remission. Only 1 pt in the ND underwent SCT in first remission (due to persistent MRD positivity), and no relapses have been observed. The 2-year EFS and OS rates in the ND cohort are 93%. Among the 13 responding pts in the R/R cohort, 6 (46%) underwent SCT. The 2-year EFS and OS rates for the R/R cohort are 42% and 61%, and for the CML-LBP cohort are 33% and 60%, respectively. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to recurrent neurotoxicity. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission. Clinical trial information: NCT03263572. [Table: see text]

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

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

Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial

Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome.

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

ALL-174: Analysis of Elderly Patients (≥70 Years Old) with Acute Leukemia in the Era of Targeted Therapy

Background Analysis of SEER database shows that the median age of acute myeloid leukemia (AML) patients at diagnosis is 68 years, with ~1/3 of patients older than 75 years. Although acute lymphoblastic leukemia (ALL) is mainly a disease of the younger population, ~12% of patients are older than 65 years old at diagnosis. Elderly patients suffer from increased toxicity compared to younger patients translating into a need for reduction in chemotherapy dose intensity as well as a higher rate of early death. Elderly patients, 70 years of age and older, receiving intensive chemotherapy have an extremely poor outcome with reported median overall survival (OS) of approximately 4 months in ALL and 6-12 months in AML. Within the last couple of years a flurry of targeted therapies has been introduced into clinical practice and new treatment opportunities for older patients have become available. We sought to investigate the pattern of targeted therapy utilization and clinical trial enrollment in the older patients with acute leukemia in our center. Methods A single center retrospective analysis of patients aged ≥ 70 years with newly diagnosed acute leukemia treated at a the hemato-oncology admission unit in a large tertiary center between 4/2011 and 4/2019. Results 52 patients [AML (n=44 including 3 acute promyelocytic leukemia), ALL (n=5), mixed phenotype acute leukemia (n=2) and blastic plasmacytoid dendritic cell neoplasm (n=1)] were included in the analysis. 44% of the entire cohort received novel approaches with 26.9% of patients enrolled in clinical trials and 30.7% receiving targeted therapy in the off-trial setting (in all lines of therapies). Due to the small cohort of non-AML patients, we present herein in detail the results of the non-APL AML patients only (Table 1). Most of the AML patients had high-risk features such as therapy related AML (n=12), AML with myelodysplastic-related changes (n=9). Adverse risk cytogenetics was observed in 13 patients. 17 patients (41%) received intensive chemotherapy, mainly the “3+7” induction regimen with daunorubicin 60mg/m2/day. 58.6% were considered ineligible for intensive chemotherapy due to age and comorbidities, third of those patients were enrolled into clinical trials, and two-thirds received either Azacitidine alone, LDAC alone, or in combination with venetoclax. The most used targeted agent was venetoclax (combined with either azacytidine or LDAC) which was given to 12 patients (all lines of therapies) achieving 1-year OS of 50%. The complete remission (CR) rate for patients receiving intensive chemotherapy was 41% and the 1-year OS was 47.1% with a median OS of 10.3 months compared to 37.5% CR and a median OS of 3.7 months for patients receiving non-intensive therapy (95% CI, 1.4-6, p=0.072, Figure 1a). Patients who received either targeted therapy or were enrolled upfront into a clinical trial had a 1-year OS of 44.4%. Four patients, median age of 73.5 years (70.7-73.7 years), underwent hematopoietic stem-cell transplantation in first remission , receiving non-myeloablative conditioning, with median OS of 75% at 1 year of follow-up. In a subgroup analysis of octogenerians (≥ 80 years old), all 11 patients were diagnosed with AML, and 63% of them had either therapy-related AML or AML with myelodysplastic-related changes. All received non-intensive therapy with 36% receiving either targeted therapy or enrolled into a clinical trial. Interestingly, although the1-year OS of the octogenerians was 36%, those on a clinical trial or receiving targeted therapy had 1-year OS of 91%. For the entire cohort (including non-AML patients), patients who were either enrolled into a clinical trial or received targeted therapy had 1-year OS of 47.8% with a median OS of 10.3 months compared to 37.9% and median OS of 4.2 months 1-year OS for those who did not receive targeted therapy or were not enrolled into a clinical trial (95% CI, 1.8-18.8, p=0.618, Figure 1b). Conclusions Patients over 70 years of age with acute leukemia seem to benefit from the administration of targeted therapy and/or enrollment into clinical trials compared to standard approaches. This holds true also for octogenerians. If this is not feasible, a selected group of carefully chosen patients might benefit from intensive therapy as well. Download : Download high-res image (249KB) Download : Download full-size image Disclosures Wolach: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker.

Analysis of Elderly Patients (≥70 years old) with Acute Leukemia in the Era of Targeted Therapy

Background Analysis of SEER database shows that the median age of acute myeloid leukemia (AML) patients at diagnosis is 68 years, with ~1/3 of patients older than 75 years. Although acute lymphoblastic leukemia (ALL) is mainly a disease of the younger population, ~12% of patients are older than 65 years old at diagnosis. Elderly patients suffer from increased toxicity compared to younger patients translating into a need for reduction in chemotherapy dose intensity as well as a higher rate of early death. Elderly patients, 70 years of age and older, receiving intensive chemotherapy have an extremely poor outcome with reported median overall survival (OS) of approximately 4 months in ALL and 6-12 months in AML. Within the last couple of years a flurry of targeted therapies has been introduced into clinical practice and new treatment opportunities for older patients have become available. We sought to investigate the pattern of targeted therapy utilization and clinical trial enrollment in the older patients with acute leukemia in our center. Methods A single center retrospective analysis of patients aged ≥ 70 years with newly diagnosed acute leukemia treated at a the hemato-oncology admission unit in a large tertiary center between 4/2011 and 4/2019. Results 52 patients [AML (n=44 including 3 acute promyelocytic leukemia), ALL (n=5), mixed phenotype acute leukemia (n=2) and blastic plasmacytoid dendritic cell neoplasm (n=1)] were included in the analysis. 44% of the entire cohort received novel approaches with 26.9% of patients enrolled in clinical trials and 30.7% receiving targeted therapy in the off-trial setting (in all lines of therapies). Due to the small cohort of non-AML patients, we present herein in detail the results of the non-APL AML patients only (Table 1). Most of the AML patients had high-risk features such as therapy related AML (n=12), AML with myelodysplastic-related changes (n=9). Adverse risk cytogenetics was observed in 13 patients. 17 patients (41%) received intensive chemotherapy, mainly the "3+7" induction regimen with daunorubicin 60mg/m2/day. 58.6% were considered ineligible for intensive chemotherapy due to age and comorbidities, third of those patients were enrolled into clinical trials, and two-thirds received either Azacitidine alone, LDAC alone, or in combination with venetoclax. The most used targeted agent was venetoclax (combined with either azacytidine or LDAC) which was given to 12 patients (all lines of therapies) achieving 1-year OS of 50%. The complete remission (CR) rate for patients receiving intensive chemotherapy was 41% and the 1-year OS was 47.1% with a median OS of 10.3 months compared to 37.5% CR and a median OS of 3.7 months for patients receiving non-intensive therapy (95% CI, 1.4-6, p=0.072, Figure 1a). Patients who received either targeted therapy or were enrolled upfront into a clinical trial had a 1-year OS of 44.4%. Four patients, median age of 73.5 years (70.7-73.7 years), underwent hematopoietic stem-cell transplantation in first remission , receiving non-myeloablative conditioning, with median OS of 75% at 1 year of follow-up. In a subgroup analysis of octogenerians (≥ 80 years old), all 11 patients were diagnosed with AML, and 63% of them had either therapy-related AML or AML with myelodysplastic-related changes. All received non-intensive therapy with 36% receiving either targeted therapy or enrolled into a clinical trial. Interestingly, although the1-year OS of the octogenerians was 36%, those on a clinical trial or receiving targeted therapy had 1-year OS of 91%. For the entire cohort (including non-AML patients), patients who were either enrolled into a clinical trial or received targeted therapy had 1-year OS of 47.8% with a median OS of 10.3 months compared to 37.9% and median OS of 4.2 months 1-year OS for those who did not receive targeted therapy or were not enrolled into a clinical trial (95% CI, 1.8-18.8, p=0.618, Figure 1b). Conclusions Patients over 70 years of age with acute leukemia seem to benefit from the administration of targeted therapy and/or enrollment into clinical trials compared to standard approaches. This holds true also for octogenerians. If this is not feasible, a selected group of carefully chosen patients might benefit from intensive therapy as well. Disclosures Wolach: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker.

PB1788 B‐SYMPTOMS, PERFORMANCE STATUS, AND RESPONSE TO FIRST THERAPY AS SURVIVAL PREDICTIVE FACTORS FOR PERIPHERAL T‐CELL LYMPHOMA AT PROGRESSION/RELAPSE: A SINGLE INSTITUTE ANALYSIS

Background:Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas that account for 5‐15% of non‐Hodgkin lymphomas. PTCL, not otherwise specified (PTCL‐NOS), is the most common subtype that accounts for 25.9% of PTCL, followed by angioimmunoblastic T‐cell lymphoma (AITL), NK/T‐cell lymphoma (NKTCL), Adult T‐cell Leukemia/Lymphoma (ATLL), ALK‐positive anaplastic large cell lymphoma (ALK+ ALCL), and ALK‐negative ALCL (ALK‐ ALCL) (Vose J. et al., 2008). The Prognostic Index for PTCL‐NOS (PIT; Gallamini A. et al., 2004) is a prognostic model widely used for PTCL‐NOS. There are, however, no established risk factors developed specifically for PTCL after progression/relapse.Aims:We analyzed the survival outcomes of PTCL after first progression/relapse, and report on newly identified prognostic factors for relapsed/refractory PTCL.Methods:We identified 144 patients with newly diagnosed PTCL‐NOS, AITL, ALK+ ALCL, ALK‐ ALCL, NKTCL and ATLL between 2005‐2017 in our institution. We then analyzed 57 cases with either disease progression or relapse after first line therapy (PTCL‐NOS n = 33, AITL n = 10, ALK‐ ALCL n = 4, ALK+ ALCL n = 1, NKTCL n = 9). Overall survival (OS) and progression‐free survival (PFS) were estimated, using the Kaplan‐Meier method, and then further compared by PIT groups. Additionally, possible prognostic factors were compared by log rank test. Variables that remained significant in univariate analysis were incorporated in multivariate analysis using the Cox proportional hazard regression model to further investigate independent prognostic factors. For patients who underwent autologous or allogeneic stem cell transplant (SCT), response to therapy was evaluated before SCT.Results:Seventy‐nine patients (60%) experienced progression/relapse after first line therapy. After excluding patients who did not receive salvage treatment at our institution, we analyzed the remaining 57 cases with progression/relapse (PTCL‐NOS n = 33, AITL n = 10, ALK‐ ALCL n = 4, ALK+ ALCL n = 1, NKTCL n = 9). The overall response rate (ORR) and complete response (CR) rates at progression/relapse were 46% (95% CI: 32.4‐59.3%) and 25% (95% CI: 14.1‐37.8%), respectively. The median OS was 13 months (95% CI: 6‐23 months) and PFS was 3 months (95% CI: 2‐7months). There were no cases with ATLL in progression/relapse as all patients with ATLL were either too frail to receive salvage therapy after first progression/relapse, or proceeded to SCT in first remission. Neither PIT at diagnosis nor at first progression/relapse was predictive of OS after relapse. Moreover, there was no correlation between PIT and OS in an analysis limited to the patients with PTCL‐NOS. Multivariate analysis revealed that presence of B‐symptoms (HR: 4.83, 95% CI: 2.10‐11.0, P &lt; .001) and performance status (PS) greater than 1 (HR: 6.13, 95% CI: 1.84‐20.4, P = .003) were significantly associated with inferior OS. Achieving complete or partial remission after first line therapy was associated with superior OS (HR 9.34, 95% CI 0.16‐0.71, P = .003). Complete or partial remission after first line therapy was the only independent predictive factor for PFS (HR 0.31, 95% CI: 0.15‐0.65, P = .002).Summary/Conclusion:The presence of B‐symptoms and poor PS at progression/relapse were associated with poor OS. Achieving complete or partial remission after first line therapy was associated with better OS. To our knowledge, B‐symptoms and response to previous therapy have never been reported as independent prognostic factors. A study with a larger sample size and longer follow‐up period is warranted to further assess the validity of these factors.

B-Symptoms, Performance Status and Response to First Therapy As Survival Predictive Factors for Peripheral T-Cell Lymphoma at Progression/Relapse: A Single Institute Analysis

IntroductionPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of generally aggressive lymphomas that account for 5-15%of non-Hodgkin lymphomas. PTCL, not otherwise specified (PTCL-NOS), is the most common subtype that accounts for 25.9% of PTCL, followed by angioimmunoblastic T-cell lymphoma (AITL), NK/T-cell lymphoma (NKTCL), Adult T-cell Leukemia/Lymphoma (ATLL), ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), and ALK-negative ALCL (ALK- ALCL) (Vose J. et al, 2008). The Prognostic Index for PTCL-NOS (PIT; Gallamini A. et al, 2004) is a prognostic model widely used for PTCL-NOS. There are, however, no established risk factors developed specifically for PTCL after progression/relapse. We report the survival outcomes of 6 common subtypes of PTCL after first line therapy as well as after first progression/relapse, and report newly identified prognostic factors for PTCL after progression/relapse.MethodsWe identified 144 patients with newly diagnosed PTCL-NOS, AITL, ALK+ ALCL, ALK- ALCL, NKTCL and ATLL between 2005-2017 in our institution. After excluding patients who did not receive treatment in our institution, we performed a retrospective analysis of the remaining 132 newly diagnosed patients (PTCL-NOS n=47, AITL n=21, ALK- ALCL n=6, ALK+ ALCL n=9, NKTCL n=36, ATLL n=21). Furthermore, we analyzed 57 cases of first progression/relapse. Overall survival (OS) and progression-free survival (PFS) were estimated for newly diagnosed lymphoma (OS1 and PFS1) and at first progression/relapse (OS2 and PFS2), using the Kaplan-Meier method. OS1 and OS2 were further compared by PIT groups. Additionally, possible prognostic factors for OS2 were compared by log rank test. Variables that remained significant in univariate analysis were incorporated in multivariate analysis using the Cox proportional hazard regression model to further investigate independent prognostic factors. For patients who underwent autologous or allogeneic stem cell transplant (SCT), response to therapy was evaluated before SCT.ResultsThe overall response rate (ORR) for first line therapy was 74.2% (95% CI: 65.9-81.5%), with a complete response (CR) rate of 58.3% (95% CI: 49.4-66.8%). Median follow up was 26.5 months and the median OS and PFS were 43 months (95% CI: 30-57 months) and 14 months (95% CI: 8-20 months), respectively. There were significant differences in OS1 by subtype; ALK+ ALCL did not achieve the median, and ATLL fared the worst, with median OS1 of 7 months (Figure 1). There was a correlation between PIT scores and OS1 in our cohort (P < .001). Seventy-nine patients (60%) experienced progression/relapse after first line therapy. After excluding patients who did not receive salvage treatment at our institution, we analyzed the remaining 57 cases with progression/relapse (PTCL-NOS n=33, AITL n=10, ALK- ALCL n=4, ALK+ ALCL n=1, NKTCL n=9). The ORR and CR rates at progression/relapse were 46% (95% CI: 32.4-59.3%) and 25% (95% CI: 14.1-37.8%), respectively. The median OS2 was 13 months (95% CI: 6-23 months) and PFS2 was 3 months (95% CI: 2-7 months). There were no cases with ATLL in progression/relapse as all patients with ATLL were either too frail to receive salvage therapy after first progression/relapse, or proceeded to SCT in first remission. Neither PIT at diagnosis nor at first progression/relapse was predictive of OS2. Moreover, there was no correlation between PIT and OS2 in an analysis limited to only patients with PTCL-NOS. Multivariate analysis revealed that presence of B-symptoms (HR: 4.83, 95% CI: 2.10-11.0, P < .001) and Performance Status (PS) greater than 1 (HR: 6.13, 95% CI: 1.84-20.4, P = .003) were significantly associated with poor OS2. Achieving complete or partial remission after first line therapy was associated with superior OS2 (HR 9.34, 95% CI 0.16-0.71, P = .003). Complete or partial remission after first line therapy was the only independent predictive factor for PFS2 (HR 0.31, 95% CI: 0.15-0.65, P = .002).ConclusionThe presence of B-symptoms and poor PS at progression/relapse were associated with poor OS2. Achieving complete or partial remission after first line therapy was associated with superior OS2. To our knowledge, B-symptoms and response to previous therapy have never been reported as independent prognostic factors. A study with a larger sample size and longer follow-up period is warranted to further assess the validity of these factors. DisclosuresNishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Bristol myers Squib: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria.

High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML

AbstractAcute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated NPM1 in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than FLT3) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated NPM1 to evaluate the potential significance of NPM1 variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high NPM1 VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; P < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; P < .0001) compared with the other NPM1-mutated cases. In both univariate and multivariable analyses, high NPM1 VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission (P = .0004) and in patients with mutated DNMT3A (P < .0001). Our findings indicate that the prognostic effect of NPM1 mutation in de novo AML may be influenced by the relative abundance of the mutated allele.

Clinical characteristics, molecular profile and outcomes of myeloid sarcoma: a single institution experience over 13 years

ABSTRACTBackground: Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified.Objective: To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS.Methods: We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002–2015).Results: MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n = 19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n = 12), 35% for CD68 (n = 8), 30% for CD34 (n = 7), and 26% for lysozyme (n = 6). Cytogenetic abnormalities were seen in 63% (n = 12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n = 3) or monosomal (n = 2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4–24.4 months). The OS was significantly better for patients <65 years (24.6 vs. 3.4 months, p = 0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p < 0.001). All patients who underwent allogeneic hematopoietic stem cell transplant attained long-term remissions, with a median follow-up of 54 (range 32–120) months.Conclusion: Failure to achieve CR with induction therapy, and age >65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions.

The Role of Hematopoietic Stem-Cell Transplantation in First Remission in Pediatric Acute Lymphoblastic Leukemia: A Narrative Review

The Role of Hematopoietic Stem-Cell Transplantation in First Remission in Pediatric Acute Lymphoblastic Leukemia: A Narrative Review

Allogeneic Stem Cell Transplantation for Elderly Patients with Intermediate-Risk Cytogenetic Acute Myeloid Leukemia and Internal Tandem Duplication of FLT3 (FLT3-ITD); A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Introduction: The presence of an internal tandem duplication of FLT3 (FLT3-ITD) confers a higher risk of relapse and is now a current indication of allogeneic stem cell transplantation (SCT) in patients with intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) in first complete remission (CR1). Most studies encouraging this strategy have been performed in patients below 60 year-old, after a myeloablative conditioning (MAC) and using a sibling donor. Because age remains associated with a worse outcome after SCT, we decided to analyse outcomes of SCT in patients aged 60 year-old or older with intermediate-risk AML and FLT3-ITD.Methods: Using the EBMT registry, we selected de novo acute myeloid leukemia (AML) harboring IRC-AML and FLT3-ITD in patients transplanted from a related or matched unrelated donor (9/10 or 10/10) between January 2000 and July 2014.Results: Two hundred and five patients have been allocated. Median age at the time of SCT was 64 (range, 60-75) year-old and median follow-up was 20 (range, 2-139) months. Ninety-four percent of the patients had a good performance status (Karnofsky at SCT ≥ 80%). Most patients had a normal karyotype at diagnosis (90% versus 10% with other intermediate-risk karyotype) and NPM1 status was reported in 131 patients out of which 100 (76%) were mutated. Thirty-four patients received a MAC, 142 had a reduced-intensity conditioning (RIC) and 29 a non-myeloablative conditioning (NMA). One hundred forty-six patients received their SCT in first remission (CR1), 24 in second remission (CR2) and 35 in more advanced stage of the disease, respectively. The 2-year leukemia-free survival (LFS) was 52% in patients in CR1, 17% in those in CR2 and 11% in patients with advanced disease, respectively (p<0.005). Similarly, the 2-year overall survival (OS) was 54% in CR1, 24% in CR2 and 11% in advanced disease, respectively (p<0.005). The 2-year non-relapse mortality (NRM) for the all cohort was 20%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 30%.In multivariate analysis, disease status at SCT was the most powerful predictor of worse LFS and OS. Age, as a continuous variable, was not significantly associated with outcomes. Donor type (unrelated versus sibling donor) and donor CMV positivity correlated with worse OS and higher NRM. Next, we performed a second analysis focusing on patients transplanted in CR1. A multivariate analysis performed in this subgroup showed that age, as a continuous variable, did not translate into worse LFS, OS or NRM. Interval from diagnosis to CR1 was significantly associated with LFS, being 63% in patients achieving CR1 in less than 43 days and 45% in patients achieving CR1 in more than 43 days, respectively (p<0.005). NMA conditioning was associated with a trend to a worse OS.Conclusion: Allogeneic SCT in elderly (≥60 up to 75 year-old) patients with IRC-AML harboring the FLT3-ITD mutation, similar to current strategy in younger patients, appears as a good treatment strategy if performed in CR1, independently of age, with somewhat inferior outcome in transplants from unrelated donors. Nevertheless, indication for transplantation should still be evaluated taking into account donor type, co-morbidities and performance status. DisclosuresCraddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Russell:Therakos: Other: shares.

Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial.

The presence of a mutated nucleophosmin-1 gene (NPM1(mut)) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1(mut) AML eligible for allogeneic SCT in a donor versus no-donor analysis. Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1(mut) patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1(mut) AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1(mut) patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1(mut) AML with a sibling donor.