Abstract: Not only does IFN prolong the survival of CML patients, but the 10-20% of patients who achieve a complete cytogenetic remission (CCyR) with IFN have a median survival & gt;10 yrs and some of these patients may actually be cured. Imatinib mesylate (IM) has replaced IFN as front line therapy for newly diagnosed patients due to its favorable toxicity profile and superior initial response rate. Recent laboratory and clinical data suggest the impact of IM on CML stem cells may be limited, raising the question of durability of IM responses. Conversely, our data suggest that IFN is directly toxic to CML stem cells, at least in part through induction of CML stem cell terminal differentiation that also requires myeloid growth factors. IFN’s primary activity against CML stem cells rather than mature CML progenitors may explain the slow, but often durable, responses seen in IFN-treated patients, while the rapid responses induced by IM are likely to be a consequence of its impressive activity against mature CML progenitors. We report results of our clinical trial adding GM-CSF to IFN as upfront therapy to improve cytogenetic responses over IFN alone in patients with newly diagnosed CML. Patients received IFN with a goal of 5 x 106 units/m2/day and dose reductions for cytopenias. Upon achieving a hematologic response, pts started GM-CSF at 125μg/m2/day for 6 months. GM-CSF was initially dose-reduced for WBC & gt; 10,000/μL; this parameter was changed to 20,000/μL after 2 of the first 3 pts were removed from study because of persistently elevated WBC despite 2 dose reductions of GM-CSF. No further pts have been removed from the study due to increased WBC. Response was monitored every 3 months by peripheral blood FISH for bcr-abl and every 6 months by bone marrow cytogenetics and RT-PCR. A total of 58 pts were enrolled on the trial with 51 considered evaluable for response (2 unevaluable due to persistently elevated WBC and 5 pts withdrew consent before the initial 3 month evaluation) and all 58 pts for toxicity. The combination of IFN and GM-CSF was well tolerated and 12/58 (20%) of enrolled pts withdrew consent due to treatment-related toxicity. However, many pts withdrew consent prior to achieving landmark responses, including 15/58 before achieving a MCR and 15/58 prior to a CCyR. Unfortunately, these groups received a historically short course of IFN-based therapy (median 14, range 3–45, mos) in part due to the availability of IM during this trial. Interestingly, 3 pts withdrew consent despite achieving a CCyR on the combination. Only 2 pts came off study due to progression ( & gt;35% Ph+). 35 (69%) of 51 evaluable patients obtained a MCR (Ph+ & lt; 35%) at a median of 3 (range 3 – 15) months with over 1/3 of them achieving a CCyR at a median of 9 (range 3–21) months. An additional 13 pts in a MCR on IFN + GM-CSF achieved a CCyR after switching to IM because of patient preference. Thus, 51% (26/51) of evaluable patients on this trial are currently in a CCyR at a median follow-up of 4.3 (range 3–6) years. IFN + GM-CSF appears to be more active in CML than IFN alone, inducing a MCR in nearly 70% of patients. The incidence of CCyR with this combination is difficult to determine because many of the patients switched to IM while still responding to IFN. Because IFN + GM-CSF appears to target CML stem cells, while IM may not, this combination should be considered as part of the treatment algorithm for CML.

Abstract: Background: Contemporary trials in adult Ph+ ALL patients with TKIs continue to show improved outcomes with allogeneic blood or marrow transplantation (alloBMT) in first remission (CR1) (Chalandon. Blood. 2015 AND Ravandi. Blood Adv. 2016). These studies have relied on myeloablative conditioning (MAC) and largely required an HLA-matched donor. Post-transplant survival in Ph+ ALL has been shown to be similar between patients transplanted with reduced-intensity conditioning (RIC) and MAC, but the incidence of relapse after RIC is higher (Bachanova. Leukemia. 2014). Post-transplant TKI maintenance reduces the incidence of relapse (Brissot. Haematologica. 2015), but this strategy has not specifically been investigated after RIC. Additionally, HLA-haploidentical donor transplants using post-transplant cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis have comparable outcomes to HLA-matched transplants (McCurdy. Haematologica. 2017). We analyzed outcomes among patients who universally received PTCy and attempted post-transplant TKI prophylaxis to determine the importance of remission status (CR1 vs. later), conditioning regimen, donor type, and TKI choice. Methods: The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using PTCy between January 2008 and August 2018. Characteristics of patients were summarized and compared using the student's T test for continuous variables and Fisher's exact test for categorical variables. Estimators of OS and RFS were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model. Results: A total of 81 transplants for Ph+ ALL were performed: 69 (85%) in CR1 and 12 (15%) in second or greater remission (CR2+). The demographics are presented in Table 1 and separated by conditioning regimen [MAC vs. nonmyeloablative (NMAC)] for transplants in CR1. The cumulative incidences of grade 2-4 and grade 3-4 aGVHD at 1 year were 33% (95% CI, 23% to 44%) and 9% (95% CI, 3% to 15%), respectively. The incidence of moderate or severe cGVHD at 2 years was 8% (95% CI, 2% to 13%). Nearly all patients (91.4%) initiated a post-transplant TKI at a median of 56 days. Overall, 44.4% of patients were able to take a TKI on ≥85% of nonrelapse days from day 31-395 post-transplant. AlloBMT in CR1 (compared to CR2+) improved RFS (HR=0.25, p=0.0002) and pre-transplant minimal residual disease (MRD) by flow cytometry (MFC) was associated with decreased RFS (HR=2.57, p=0.039). The presence of pre-transplant MRD by PCR did not confer an increased risk of relapse (HR 1.12, p=0.84). Among the 69 patients transplanted in CR1, the 5-year OS was 77.6% (95% CI, 64.8% to 86.2%) and RFS was 67% (95% CI, 52.4-76.5%). As shown in Figure 1, the use of NMAC versus MAC (HR 0.37, p=0.02) and dasatinib versus imatinib at diagnosis (HR 0.21, p=0.007) led to improved relapse-free survival (RFS) in univariate analyses. Neither donor type (with the majority being haploidentical) nor recipient age ≥60 affected RFS. Post-transplant TKI prophylaxis was discontinued prior to relapse in 20 patients among whom 12 remain in an MRD-negative remission, 4 died of non-relapse causes, 3 relapsed, and 1 developed recurrent MRD controlled by a TKI. The median duration of post-transplant TKI prophylaxis prior to discontinuation was 46.5 months in those who remain in treatment-free remission versus 15.6 months in those who relapsed (p=0.01). Eighteen relapses occurred on maintenance therapy, and 90% of tested cases were positive for a kinase domain mutation conferring resistance to the TKI in use at relapse. No significant difference in the median time to TKI initiation post-transplant was noted between those who relapsed on maintenance and those who did not (70 days vs. 55 days, p=0.6). All patients in ongoing remission were MRD-negative by PCR at their most recent evaluation. Conclusions: AlloBMT with PTCy in Ph+ ALL was most effective when performed in CR1 with negative MFC for MRD. The initiation of post-transplant TKI prophylaxis was nearly universal. Among patients transplanted in CR1, the best results were achieved in patients treated with dasatinib at diagnosis (5-year RFS 83%) and NMAC (5-year RFS 73.1%). Thus post-transplant TKI prophylaxis appeared to overcome any relapse control advantage for MAC, yielding better outcomes with NMAC. Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding; Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy. DeZern:Abbvie: Consultancy; Astex: Research Funding; MEI: Consultancy; Celgene: Consultancy, Honoraria. Pratz:Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; AbbVie: Other: Scientific Advisory Board, Research Funding. Levis:Astellas: Honoraria, Research Funding; Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Gojo:Amgen: Research Funding; Merck: Research Funding; Genentech: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amphivena: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Dalton:Eli Lilly: Research Funding; AbbVie: Research Funding. Jain:Takeda: Consultancy, Honoraria; Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age & gt;60 (33.3% vs. 29.2%, p & gt;0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen & lt;150) prior to treatment initiation (4.8% vs. 8.3%, p & gt;0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p & gt;0.99). Table 1 compares the time to ANC recovery & gt;500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

Abstract: Posttransplantation cyclophosphamide is effective as sole GVHD prophylaxis for myeloablative HLA-matched–related or –unrelated BMT. Despite low chronic GVHD with PTCy, relapse and survival are comparable with outcomes reported using other GVHD prophylactic approaches.

Abstract: Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

Abstract: Background: Patients with acute myeloid leukemia (AML) presenting with hyperleukocytosis have frequent complications and early mortality. Pulmonary, central nervous system, and cardiovascular complications are common. Attempts to improve outcomes in the 10% of AML patients arriving with hyperleukocytosis have included leukapheresis. No prospective randomized study has supported the use of leukapheresis, and retrospective reports have revealed persistently poor outcomes as well as emerging concerns of acquired coagulopathy and worsening hypoxemia after leukapheresis. While many centers use a leukapheresis protocol processing two blood volumes, Johns Hopkins protocol routinely processes three-five blood volumes. This study aimed to assess coagulopathy, hypoxemia, and mortality with large volume leukapheresis. Methods: 32 patients with newly diagnosed AML treated with large volume leukapheresis for WBC depletion are included in this report. Demographic, clinical, laboratory, and apheresis-related data were collected. Coagulopathy and hypoxemia-related metrics were evaluated within 6 hours before leukapheresis and within 6 hours of completion of leukapheresis. Descriptive and inferential statistics (chi square and Mann-Whitney U test) were used to compare pre and post-leukapheresis findings and assess clinical outcomes. Results: Twenty-nine of 32 (93.8%) patients presented with symptomatic leukostasis (with pulmonary and/or CNS symptoms in 26/29). Median blood volume processed was 14.8 liters (range 4-23.4L). Mean platelet count decreased from 60x109/L to 37x109/L after leukapheresis (p 〈 0.001). Comparing supplemental oxygen requirements before and after leukapheresis, 1 patient had decreased requirements, 6 increased, and 25 were unchanged. Median change in prothrombin time (PT) was an increase of 1 second (range: -2.4 to +7.7 seconds; p=0.13). Twenty-six of 26 evaluable patients had a decline in fibrinogen post-pheresis, with median reduction of 84 mg/dL (range: -12 to -483 mg/dL; p=0.04). Twelve of 18 (66.7%) patients 65 years and older died by day 30, compared with 3/14 〈 65 years-old (p=0.01). Fifteen of 32 (46.9%) arrived with acute renal failure on admission, 10 of whom died by day 30. All 8 patients requiring hemodialysis during their initial admission died prior to day 30. 12/32 (37.5%) required mechanical ventilation, 10 of whom died by day 30. Overall, 10/32 (31.3%) died by day 7, and 15/32 (46.9%) died by day 30. The most common primary cause of death was multiorgan failure including both renal failure and hypoxemia in 8 patients. Two patients died of confirmed intracranial hemorrhage, and 2 died with clinical suspicion for intracranial hemorrhage but were too unstable for imaging prior to death. Two deaths were attributed to ischemic stroke, and 1 patient died with isolated refractory hypoxemia. Conclusions: Patients with AML presenting with hyperleukocytosis have a very high mortality, particularly when complicated by symptomatic leukostasis. Similar to Van de Louw's report, we observed worsening coagulopathy and a subgroup with increased oxygen requirements after leukapheresis. While our sample size is too small to draw broad conclusions, we were not able to identify a group clearly benefiting from leukapheresis. We did not find evidence that larger volume leukapheresis decreased complications or mortality. These results should lead to caution when considering leukapheresis for patients with newly diagnosed AML, particularly in those presenting with a severe coagulopathy. Table Disclosures Webster: Pfizer: Consultancy; Amgen: Consultancy; Genentech: Research Funding. Gojo:Amphivena: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Pratz:Boston Biomedical: Consultancy; Millenium/Takeda: Research Funding; Agios: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Smith:Celgene: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Novartis: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Levis:Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria.