Complete Cytogenetic Remission Research Articles

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

Five-Year Follow up Results of Phase II Clinical Trial Evaluating Ruxolitinib (RUX) and Azacitidine (AZA) Combination Therapy in Patients (pts) with Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

Introduction: MDS/MPN represent a distinct category of Philadelphia chromosome negative myeloid neoplasms that share pathological and morphological characteristics with both MDS and MPN. Very few prospective studies have been conducted in pts with MDS/MPN, with currently available data showing a median overall survival (OS) of less than two years in this challenging subset. We conducted a phase 2 clinical trial evaluating the combination of JAK-inhibitor RUX with demethylating agent AZA in pts with MDS/MPN. The interim analyses (Assi et al, AJH 2018) showed objective responses in 57% pts and a median duration of response (DOR) of 8 months (mos). Herein we report the long-term follow up of a larger cohort of pts treated on this prospective ongoing clinical trial. Methods: We conducted an open label single-arm phase 2 clinical trial (NCT01787487) at the MD Anderson Cancer Center, Houston, evaluating the use of RUX-AZA in newly diagnosed or previously treated MDS/ MPN. Adults aged ≥ 18 years with MDS/MPN categorized as Intermediate 1-2 or High-risk by Dynamic International Prognosis Scoring System (DIPSS) (Passamonti et al, Blood 2010) were included. Pts previously exposed to RUX and/or AZA were excluded. RUX 5-20mg twice daily (per RUX label depending upon platelet counts at initiation) was given in 28-day cycles, and AZA 25mg/m2 (SQ or IV) Days 1- 5 was added starting cycle 4. Cycles were repeated every 4-6 weeks depending on count recovery. Response assessment was carried out using the 2015 International Consortium Proposal of response MDS/MPN criteria (Savona M et al, Blood 2015) and best objective response was tabulated. Progression free survival (PFS) included treatment change because of disease progression or inadequate response, transformation to acute myeloid leukemia (AML) or death and calculated from the time of therapy initiation. Results: From May 2013 to August 2022, 52 pts with a median age of 68 years (range, 39-82 years) were treated on trial. The data cutoff was July 15, 2023 ( Table 1). 32 pts (61%) were males, and 9 (75%) pts were white. 50 pts (96%) had ECOG PS<2. Baseline median bone marrow (BM) blasts were 4.5% (range 0-19%), with 19 (37%) carrying JAK2 mutations, and 16 (31%) with an abnormal karyotype. Intermideate-2 DIPSS was the most prevalent risk category, seen in 23 (44%) pts. At least one cytopenia was present in 32 (61%) pts, and three (6%) pts had bicytopenia. 24 of 49 (49%) had palpable splenomegaly, and 3 pts had undergone prior splenectomy. After a median follow up of 60 months (mos) (95% CI: 50.0-71.3) from therapy initiation, 18 (35%) pts are alive, and 1 pt is on active trial therapy. Objective responses per the MDS/MPN international consensus response criteria were observed in 28 (54%) pts and included clinical improvement in 14 (50%) pts, partial marrow response in 12 (43%) pts, optimal marrow response and cytogenetic complete remission in 1 (4%) pt each. The DOR in the 28 pts with objective response to therapy (censored for death in pts who died without evidence of progression) was 35 mos (95% CI: NE-73.5). The median OS in this group of responders was 36.4 mos (95% CI: NE-77.2). Five of these pts died without confirmed disease progression at the time of death. For the full cohort the median PFS was 13.4 mos (95% CI: 7.9-18.8) and median OS was 31.8 mos (95% CI: 18.5-44.9 ) (Figure 1). Transformation to AML occurred in 12 (23%) pts, with the median time to transformation being 13.2 mos (range 2.9-71.3) and all of them have died at the time of last follow-up. 8 (15%) pts underwent allogenic stem cell transplant (ASCT) as subsequent therapy following treatment with AZA-RUX amongst whom 6 (75%) had shown objective responses prior to transplant. For the pts who underwent ASCT, median PFS from the initiation of AZA-RUX was 40.8 months and median OS was not reached. Conclusion: Long term follow up from this phase II prospective clinical trial demonstrates durable disease responses with the RUX-AZA combination in MDS/MPN, with the responses translating into improved survival outcomes.

Benefit of TKI-Treatment in CML after Failing Molecular or Cytogenetic Milestones

No information is available on long-term survival of tyrosine kinase inhibitor (TKI)- treated patients failing the response milestones as defined by the European LeukemiaNet (ELN). Such information would help with decision making in failing patients when risks associated with comorbidities, drug toxicities or transplantation preclude switching to another TKI or other treatments. To systematically analyze survival after reaching, or not reaching, ELN-response milestones, 1342 imatinib-treated patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular and cytogenetic tests were studied. Survival was analyzed by landmark analyses at 3, 6, 12 and 24 months and followed up to 14 years. In patients who failed the failure milestones (>10% BCR::ABL1 IS at 6 months, >1% BCR::ABL1 IS at 12 months), 10- to 12-year survival ranged around 70%, 10-20% less than in responding patients. An example is shown in Fig. 1a which depicts survival of patients reaching, or not reaching 1% BCR::ABL1 IS at 12 months. Similar survival curves were observed for the other landmarks that indicate failure. Inbetween response rates of >1%-10% BCR::ABL1 IS at 12 months indicated survival probabilities similar to those of patients failing 1% BCR::ABL1 IS, whereas patients reaching >1%-10% BCR::ABL1 IS at 24 months showed a survival similar to that of patients failing 10% BCR::ABL1 IS. Switching to alternative therapies, mostly to dasatinib and nilotinib, was observed in 372 patients (26.9%) and did not change the main results. Although cytogenetic tests were increasingly replaced by molecular tests in the course of the study, sufficient cytogenetic analyses were available for comparison with molecular analyses. Complete and partial cytogenetic remissions have been shown to be roughly equivalent to 1% and 10% BCR::ABL1 IS, respectively. Wheras reaching, or not reaching cytogenetic and molecular reponse markers at 6 and 12 months was equivalent, not reaching a complete or partial cytogenetic remission at 24 months identified a small subgroup of patients (5.9%) with inferior survival (Fig. 1b). Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios for early death. Hazard ratios at 10% BCR::ABL1 IS by 6 months were 4.0 (95%CI:2.0-8.1) for the younger patients, but only 0.9 (95% CI: 0.4-1.8) for the elderly. The reasons for early death in the younger patients were mostly CML-related, whereas the elderly primarily died of other reasons. The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualized decisions, if failing patients are confronted with risks of alternative treatments.

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (<15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Treatment Free Remission (TFR) “for” Pregnancy. Overview and Outcome of Pregnancies Reported in the Italy-Tfr Registry

TFR is a consolidated practice and the goal to be reached for all CML patients. In Italy only a few centers participate in TFR clinical trials, while, in clinical practice, many patients discontinue TKIs for intolerance, pregnancy, or other reasons. A cohort of 467 Italian patients who underwent discontinuation outside of clinical trials were collected in the Italy TFR registry. This cohort showed a mean TFR rate of 73% at 12 months. Italy-TFR is an observational study, both retrospective and prospective, with the purpose of collecting data on patients with Ph+, chronic phase CML who discontinue TKIs in an off-protocol setting. Eligibility criteria include patients treated with TKI monotherapy or in association with other drugs (IFN, BCR:;ABL1 peptidic vaccine, and others) and those who discontinued therapy for any reason. Deep Molecular Response (DMR) defined as MR4 (BCR::ABL ratio ≤ 0.01% IS), MR4.5 (≤ 0.0032%) or MR5 (≤ 0.001%) was confirmed at least three times before TKI discontinuation. Data from patients discontinuing in less than DMR were collected and analyzed separately. Molecular responses were assessed by qPCR; tests were performed by the GIMEMA Laboratories Network (LabNet). TFR was assessed using the Kaplan-Meier method and 95% confidence interval, from the date of TKI discontinuation to the date when therapy was reinitiated. Patients discontinuing for pregnancy were analyzed in this sub-analysis. Thirty patients and 33 pregnancies (3 patients had 2 pregnancies) were entered from 8/32 participating centers. Main data are reported in Table 1. Median age at diagnosis was 28 years (range 19-36), and 35 years at pregnancy (range 29-41). Fifteen patients switched from 1st to 2 ndG TKI before pregnancy due to intolerance or resistance/unsatisfactory responses. Only one patient switched to another TKI to deepen the response before attempting a second pregnancy (imatinib to nilotinib). Not all patients at TKI interruption were in DMR, however, they were all treated with the last TKI for a median of 60 months (range 18-151), and exposed to any TKI for a median of 89 months (range 44-186). Specifically, 9/33 pregnancies started in MMR (≤0.1% transcript), 13 in MR4, 6 in MR4.5, and 5 in MR5. Three patients stopped TKI therapy before conception, two at 5 months and 1.5 months, respectively, before pregnancy. The third patient, in TFR after the first pregnancy, conceived a second child while still in TFR. These 3 patients were in TFR for 9, 9 and 5 years after treatment stoppage. During pregnancy 4 patients were treated after losing MMR. One patient, in MR5 with imatinib for 4 years rapidly lost MMR and was treated with a peptidic vaccine, maintaining complete cytogenetic remission until delivery; 2 patients were treated with IFN, and 1 restarted nilotinib at 23 weeks. All 33 pregnancies were carried to term, with unremarkable outcomes for mothers and babies. No CML progression was recorded. Breastfeeding was allowed for patients with stable transcript levels. With a median follow-up of 40 months, 11 patients were still in TFR (33%; 48% at 12 months), with no differences for patients treated with imatinib or a 2 ndG TKI. The lower number of patients maintaining TFR compared with the general population of patients studied can be explained by 3 main considerations. First, 9/33 pregnancies started in MMR, which is not a criteria that allows for discontinuation, the kinetics of transcript rise are often not correlated with molecular remission. Second, the biological clock in women can rush conception attempts before the appearance of a consolidated response (also resistant patients). Third, as demonstrated in the main study, older age is the only statistically significant positive prognostic factor, with a higher risk of relapse for younger patients. Indeed, all patients restarting treatment regained at least MMR within 3 months. Except for the patient described earlier, and a patient who had a suboptimal response to the 2nd line and switched to bosutinib 3rd line, patients recommenced the same TKI discontinued before pregnancy. There was no significant difference in TFR between patients who discontinued imatinib 1 st versus 2 nd lines (Fig.1) and also in patients who discontinued 2 ndG TKI frontline versus 2 nd line for intolerance/resistance unsatisfactory response. The Italy-TFR protocol is still enrolling in the prospective cohort and updating. We plan to include more cases and present an exhaustive analysis.

Clinical Outcomes of Patients with Chronic Myeloid Leukemia and COVID-19 Infection-A Single Center Survey.

Background: Previous research has shown different effects of hematological malignancies on the outcome of patients with COVID-19 infection depending on the type of disease and the treatment received. This research was aimed at examining the clinical outcome of COVID-19 infection in positive patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Methods: We collected retrospective information on chronic myeloid leukemia patients who were treated and monitored in our institution during the pandemic period. Within this cohort, we recorded COVID-19 positive symptomatic patients and analyzed their basic characteristics, symptoms, severity, and outcome. Results: In the study cohort when COVID-19 was diagnosed, 86.7% of patients were on first-generation tyrosine kinase inhibitors therapy-imatinib. At the time of infection, 70% of patients were in molecular remission, 23.4% in complete cytogenetic remission, and 3.3% in complete hematological response. Most patients had symptomatic disease. Within the analyzed group, 56.7% of patients had asymptomatic/mild COVID-19 infection, 23.3% of patients had moderate symptoms which did not require hospitalization, and 20% of patients had severe/critical symptoms that required admission to the intensive care unit. More than half of the patients interrupted treatment with tyrosine kinase inhibitors temporarily during COVID-19. There were no deaths due to COVID-19 infection. Conclusions: In compliance with other larger clinical studies, analysis of the clinical outcome of COVID-19 infection in patients with chronic myeloid leukemia on tyrosine kinase inhibitors therapy in this study showed that they do not have an increased risk for COVID-19 infection and that they have a mild course of the disease with recovery.

Therapy in Patients with Chronic Myeloid Leukemia Outside of Clinical Trials: Results of the German CML-Registry (CML-VI)

Introduction: Tyrosine kinase inhibitors (TKI) have significantly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase (CP). With the introduction of 2nd and 3rd generation TKI, the options in the management of CML have increased. In clinical trials, 25%-50% of patients do not remain on initial treatment due to intolerance or inefficacy. Information outside of clinical trials is limited. Aim: The aim of this study is to analyze the use of different TKI in first-line treatment and the frequency of TKI switches in CML in real world. Methods: Patients with newly diagnosed CML between 1.1.2013 and 31.12.2019 were registered and followed annually up to 31.12.2021. Primary endpoint was the time to and reason for switching of any first-line treatment including treatment free remission (TFR)attempt. Further endpoints were progression-free survival (PFS), overall survival (OS), cytogenetic and molecular response. Analyses were performed using Kaplan-Meier estimates with SPSS. Results: 540 adult patients have been registered from 91 centers, 512 were evaluable. 281 patients (55%), were treated by resident oncologists, 231 patients (45%) in hospitals including 82 patients (16%) in university hospitals. 271 patients (53%) were male. At diagnosis, median age was 59 (range 16-100) years. The median follow-up was 67 (3-108) months. Information on first-line TKI treatment was available for 480 patients: 203 patients (42%) were treated with imatinib, 137 (29%) with nilotinib and 140 (29%) with dasatinib. TKI switch was reported in 155 cases (31%) after a median of 11 (0-68) months. Reasons for switching was failure in 49 patients (32%), intolerance in 88 patients (57%), and 18 patients (11%) switched TKI because of other reasons (study inclusion, desire to have children, patient request, unknown). 33 patients (7%) switched TKI more than once. 13 (8,4%) of the 155 patients with TKI-switch died during follow-up, whereas only 16 of 325 (4,9%) patients without TKI-switch. OS of patients with TKI-switch was 90%, of patients without TKI-switch 94% after 6 years. TKI stop for more than one month has been reported in 118 patients (24%) due to different reasons (attempt for TFR, intolerance, patient wish, pregnancy). 61 patients (12%) started a TFR attempt after a median of 46 (10-96) months of TKI treatment. Discontinuation criteria were not always met. Only 10 patients (6,5%) with TKI-switch started a TFR attempt compared to 51 patients (16%) who had only been treated with one TKI. 501 patients were in CP at diagnosis, 11 patients in accelerated phase (AP) and 2 patients in blast crisis (BC). Progression occurred in 9 patients (BC n=6, AP n=3) after a median time of 12 (9-22) months. Overall, AP and BC were diagnosed in 22 patients (2,3%). Of the total cohort, 29 patients died, OS was 93% after 6 years. An evaluable cytogenetic examination was carried out in 291 patients (57%) at diagnosis or in the course of disease. No statements can be made about achieving of complete cytogenetic remission as follow up results were only available in 15% and monitoring was carried out using RQ-PCR in most patients. A major molecular response (MMR, BCR::ABL1 <0.1%) was reached by 422 patients (85%), a deep molecular response (defined as BCR::ABL1 ≤0.01) by 365 patients (74%) within the follow-up period. Cumulative incidence calculation and study of patients who lost their MMR are ongoing. There is no information about the molecular status of 18 patients. Conclusion: Results of the CML VI-registry provided information on treatment but also on baseline characteristics and diagnostic parameters of CML patients in real world. The median age of the patients at diagnosis was higher than in other clinical trials. In routine care, data demonstrated high switching rates of first-line treatment and frequent TFR attempts without meeting the guideline criteria. OS rates were as high as in clinical trials and confirm normal life expectation of CML patients. MMR was reached in 85% and DMR in 74% in this population. Progression is rare. In conclusion, the CML-registry offers importing data confirming a good outcome of response and survival for CML patients outside of clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NUP98-HOXA9 Bearing Acute Myeloid Leukemia

Acute myeloid leukemia (AML) with NUP98-HOXA9 fusion gene is rare, which is caused by t(7;11)(p15;p15). Not only the prognosis is poor, the efficacy of conventional induction regimen is also barely satisfactory. Here we report two cases of NUP98-HOXA9 bearing AML. Patient 1 was a 54-year-old female. In September of 2019, she felt fatigue with complete blood count (CBC) result of leukocytes 246.78× 109/L, hemoglobin 81g/L, and platelet 119 × 109/L. Peripheral blood smear showed 5% blast cells, and bone marrow (BM) smear demonstrated AML-M5. Chromosome 46, XX, t (7; 11) (p15; p15) [20], NuP98/HOXA9 fusion gene, EVI1 expression, FLT3-ITD and KRAS mutation was also found in her BM. One course of standard induced chemotherapy regimen IA reached CR, with MRD＜10-4, low expression of EVI1, and FLT3-ITD(-)，normal chromosome, but NuP98/HOXA9（+）. After the second course of IA, relapse occurred partly due to delayed admission under the influence of COVID-19. Reinduction with IA, azacytidine +HE, FLAG regimen failed to reach remission, and the patient died of bone marrow suppression and gastrointestinal bleeding. Patient 2 was a 65-years-old male. In September of 2019, he suffered from fatigue and CBC showed leukocytes 2.52× 109/L, hemoglobin 36g/L and platelet 139 × 109/L. Peripheral blood smear showed immature cells of 7%, and his BM smear demonstrated AML-M4. Chromosome 46, XY, t (7; 11) (p15; p15) [18]/46, XY[1], NuP98/HOXA9 fusion gene and IDH2 R140Q mutation were found in the patient. He had a history of chemotherapy for small cell lung cancer. After induced by regimen of DIAG, DHEG and DCAG successively, he did not reach remission. Repeated fever and lung infection occurred during the course of the disease. He was discharged automatically due to the progression of lung cancer. NuP98/HOXA9 bearing AML is more common in young Asian women, and the majority is type M2. The two patients in this report were older with M4 or M5 type, which was rare in this kind of leukemia. NuP98/HOXA9 is a poor prognostic factor for AML. Patient 1 could reach cytogenetic CR after IA induction, relapsed before transplantation, and the effect of reinduction therapy was poor; Patient 2 did not achieve remission. It is suggested from the these patients that patients with NuP98/HOXA9 bearing AML should undergo hematopoietic stem cell transplantation as soon as possible after CR with intensive therapy if their physical conditions permit.

MDS-445 Magrolimab In Combination With Azacitidine for Patients With Untreated Higher-Risk Myelodysplastic Syndromes (HR MDS): 5F9005 Phase 1b Study Results

Magrolimab is a monoclonal antibody blocking CD47, a "don't eat me" signal overexpressed on cancer cells, which leads to tumor phagocytosis and is synergistic with azacitidine. A high unmet need exists to build on current standard-of-care azacitidine in patients with HR MDS. Report final safety/tolerability and efficacy data. Ph1b trial of magrolimab+azacitidine (NCT03248479). 95 patients with untreated HR MDS (intermediate, high, or very-high risk per the Revised International Prognostic Scoring System [IPSS-R]). Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle). Primary endpoints were safety/tolerability and complete remission (CR) rate. Median age was 69y [range, 28-91y]). IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21% of patients, respectively. Therapy-related MDS, TP53 mutation, and poor-risk cytogenetics were reported in 22%, 26%, and 62% of patients, respectively. Median number of cycles was 6 (range, 1-27). The most common treatment-emergent adverse events (TEAEs) included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (43%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and white blood cell count decreased (30%). Six patients discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline at first post dose sample was -0.7 g/dL (range, -3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%; 31% of OR-evaluable patients with baseline abnormal cytogenetics had cytogenetic CR. Median time to first OR, duration of CR, duration of OR, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. 12- and 24-month overall survival (OS) rates were 75% and 52%, respectively; median OS was not reached with 17.1 months of follow-up. Favorable outcomes were observed in patients with TP53 mutation (n=25; CR rate, 40%; median OS, 16.3 months) and wild-type TP53 (n=61; CR rate, 31%; median OS, not reached). Magrolimab+azacitidine was well tolerated, with promising efficacy in patients with untreated HR MDS, including those with TP53-mutated and -wild-type disease. A Ph3 trial of magrolimab/placebo+azacitidine (ENHANCE; NCT04313881) is ongoing.

Clinical Efficacy of Dasatinib in the Treatment of Chronic Myeloid Leukemia (CML) Patients with Different Clinical Stages

Objective: To study the efficacy of dasatinib treatment in different clinical stages of patients with chronic myeloid leukemia (CML). Methods: A total of 80 patients with chronic myeloid leukemia (CML) were selected for experimental research. According to different clinical stages, they were divided into chronic phase, accelerated phase and blast phase, and all of them were treated with dasatinib. Results: The complete cytogenetic response remission rate, complete hematologic remission rate, and major molecular biological remission rate in the chronic phase were significantly higher. Besides, the overall survival time and relapse-free survival time in the chronic phase were significantly longer, and the mortality during the follow-up period in the chronic phase was also significantly higher. Furthermore, the incidence of hematological adverse reactions of grades ? to ? in the chronic phase was significantly lower compared with the corresponding data of patients in the accelerated phase and blast phase with P&lt;0.05. Conclusion: Different clinical stages of CML patients have different curative effects of dasatinib, which can effectively treat patients in chronic stage.

Clinical Effect of Imatinib, Nilotinib, and Dasatinib on Chronic Myeloid Leukemia in Chronic Phase

The study was conducted to explore the effect of imatinib, nilotinib, and dasatinib in the treatment of chronic myeloid leukemia (CML) patients. Around 66 patients with CML in chronic phase were selected, subsequently the patients were subdivided into 3 groups with 22 patients in each group: Group A were treated with imatinib; Group B were treated with nilotinib; and Group C were treated with dasatinib. The study showed that, at 18 months of treatment, compared with group A, the molecular biology remission rates of group B and group C were significantly higher, p&lt;0.05; at 6 months and 18 months of treatment, compared with group A, the complete cytogenetic remission rates of group B and group C were significantly higher, p&lt;0.05; and compared with group A, the incidences of vomiting, headache and edema in groups B and C were significantly lower, p&lt;0.05. However, no significant different p&gt;0.05 were observed in the complete hematologic remission rates, and the incidences of neutropenia and thrombocytopenia among the three groups. In summary, nilotinib and dasatinib are effective in the treatment of patients with CML in the chronic phase, which is significantly better than imatinib treatment.

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, persistent peripheral blood cytopenias, and an increased risk of transformation to acute myeloid leukemia (AML).1 Treatment with lenalidomide has been recommended for patients with MDS and 5q deletion with symptomatic anemia and a high-transfusion burden with red blood cells (RBC) by several guidelines.2–4 Little is known about usage, chances, and challenges in daily clinical practice to comply with these guidelines. To close this informative gap an observational, multicenter, national registry, involving the whole spectrum of hematologists and oncologists from primary to tertiary health care centers in Switzerland—the Swiss Lenalidomide in MDS del(5q)-Registry (SLIM-Registry)—was established. The SLIM-Registry is a web-based clinical data management application. Data entry was performed retrospectively, after at least one cycle of lenalidomide has been applied, and locally by each participating center via a password-protected log-in at the website (www.slim-registry.ch). Eligible patients were 18 years of age or older and had a MDS and a del(5q) with or without additional cytogenetic abnormalities. Patients were either treated with lenalidomide in the past or treatment with lenalidomide was ongoing at entry into the registry. All living patients provided written informed consent. Patients with MDS without a confirmation of del(5q) were not eligible. The SLIM-Registry was carried out according to all applicable national and local regulatory requirements. There was a regular review and verification of recorded data. From March 1, 2014, until December 31, 2019, patients were included. Data cleaning was performed thereafter, and final database lock was on October 31, 2021. Totally 83 patients (57 females, 26 males) with MDS and del(5q) have been registered in 25 health care centers across Switzerland, which included minimum 1 and maximum 10 patients per center. The majority, 63 patients (75.9%), had a hemoglobin-level below 100 g/L. At diagnosis of MDS, in all patients, a bone marrow (BM) aspirate (with dry tap in 8 patients), and in 78 patients (94%) additionally a BM biopsy was done. Conventional karyotyping was performed in 45 patients, both conventional karyotyping and fluorescence in situ hybridization (FISH) were performed in 26 patients, and in 12 patients only FISH was done. In 72 patients, there was exquisitely del(5q) detected. With regard to RBC-transfusion dependence (TD) at diagnosis, 41 patients (49.4 %) had RBC-TD with a median hemoglobin of 81 g/L (range, 50–110 g/L). In 55 patients (66.3%), the diagnosis was myelodysplastic syndrome with isolated del(5q) according to WHO Classification 2008. Prognostic stratification was done according to IPSS, IPSS-R, and WPSS (Figure 1A–C).Figure 1.: Prognostic scoring systems at diagnosis of MDS. (A) IPSS at diagnosis of MDS, (B) IPSS-R at diagnosis of MDS, and (C) WPSS at diagnosis of MDS. IPSS = International Prognostic Scoring System; IPSS-R = Revised International Prognostic Scoring System; MDS = myelodysplastic syndromes; WPSS = WHO Classification-based Prognostic Scoring System.In total, 1714 cycles of treatment with lenalidomide were recorded. In all patients, at least one cycle of treatment with lenalidomide was given. At start of the first cycle, median hemoglobin was 87 g/L (range, 51–119 g/L), with 45 patients (54.2%) in need of RBC transfusions. Treatment with lenalidomide was initiated within 6 months after the diagnosis of MDS with a 5q deletion in 55 patients (66.3%). With regard to onset and duration of treatment response, in cycle 2 of treatment with lenalidomide, 22 patients (26.5% of the total cohort and 48.8% of the patients with RBC-TD at treatment start) had RBC-transfusion independence (TI), another 5 (6% and 11.1%, respectively) each in cycle 3 and in cycle 4, 2 patients (3.6% and 4.4%, respectively) in cycle 5, and 1 patient (1.2% and 2.2%, respectively) in cycle 6. Of 61 patients with at least 6 documented treatment cycles 48 patients (78.7%) had RBC-TI for ≥8 weeks. Of those, 36 patients (75%) had a diagnosis of MDS with isolated del(5q). Analyzing those 61 patients with regard to erythroid response, there were 28 patients (45.9%) with RBC-TD and a hemoglobin <90 g/L before start of treatment with lenalidomide, 16 patients (57.1%) had an erythroid response, that is, a reduction of at least 4 RBC transfusions with treatment with lenalidomide over a period of 2 months. In those 43 patients with at least 12 documented treatment cycles, 34 patients (79.1%) had RBC-TI for ≥26 weeks. The recommended dosage of lenalidomide 10 mg daily on days 1–21 of a 28-day cycle was administered in 21 patients (25.3%) without adjustments. Venous thromboembolism prophylaxis was given in 33 patients (39.8%). Of note, there were 5 patients with a treatment-free interval (TFI) for various reasons and durations (Suppl. Table S1). There was a patient who had a complete cytogenetic remission after 6 and after 12 cycles of treatment with lenalidomide. Therefore, treatment was stopped with regular monitoring of blood count and del(5q) by FISH. This patient remains in complete hematologic and cytogenetic remission 3 years after stopping treatment. Median overall survival (OS) in a multivariate analysis was significantly longer in patients who received no RBC transfusions during the first treatment cycle of 6.7 years (95% CI, 3.9-9.6) compared with patients who did receive RBC transfusions during that time of 3.34 years (95% CI, 2.56-4.12; P = 0.014), and was significantly longer in patients with MDS with isolated del(5q) of 6.7 years (95% CI, 3.0-10.4) compared with 2.4 years (95% CI, 1.99-2.9) in other entities of MDS (P = 0.004) (Figure 2A,B). With regard to Lenalidomide-emergent adverse events, there were no new safety signals identified.Figure 2.: Median OS. (A) Kaplan-Meier curve for median OS as of start of treatment with lenalidomide according to RBC transfusions during cycle 1 of treatment with lenalidomide in 61 patients with at least 6 documented treatment cycles. There was a significant longer median OS in those 30 patients who received no RBC transfusions during the first cycle of treatment with lenalidomide of 6.7 y (95% CI, 3.9-9.6) compared with 31 patients who did receive RBC transfusions during that time of 3.34 y (95% CI, 2.56-4.12; P = 0.014). (B) Kaplan-Meier curve for median OS as of start of treatment with lenalidomide according to initial diagnosis of MDS. There was a significant longer median OS of 6.7 y (95% CI, 3.0-10.4) in those 55 patients with MDS with isolated del(5q) compared with 2.4 y (95% CI, 1.99-2.9) in 28 patients with other entities of MDS (P = 0.004). CI = confidence intervals; MDS = myelodysplastic syndromes; OS = overall survival; RBC = red blood cells.In conclusion, treatment with lenalidomide was initiated within 6 months after the diagnosis of MDS with 5q deletion in about two-thirds of patients, reflecting the uncertainty with regard to the optimal time point to start disease directed treatment, especially in patients who are not—yet—RBC-transfusion dependent, as lenalidomide is formally approved only for patients with a transfusion-dependent anemia—and not for preventing it. In all patients, cytogenetic analysis at diagnosis was done. However, in 12 patients (14.5%), only FISH was performed at diagnosis, which is insufficient at initial work up. A minority of patients—14.5%—had higher-risk disease, and treatment with lenalidomide in this patient group would not entirely be in line with current guidelines. With the start of treatment with lenalidomide, 45 patients (54.2%) had RBC-TD, 22 of those patients (48.8%) were free of RBC transfusions in cycle 2, with 5 patients (11.1 %) each in cycle 3 and 4. This rapid onset of response and high efficacy with regard to RBC-TI is in line with the results of the MDS-003- and MDS-004-studies.5,6 Analyzing 61 patients with at least 6 documented cycles of lenalidomide treatment, RBC-TI for ≥8 weeks was more common in patients with a diagnosis of MDS with isolated del(5q) compared with other entities of MDS. Analyzing 43 patients with at least 12 documented cycles of lenalidomide treatment, 34 patients (79.1%) had RBC-TI for ≥26 weeks. This confirms the high efficacy of lenalidomide with regard to RBC-TI in patients with MDS and 5q deletion also in daily clinical practice.5,6 Two months before start of treatment with lenalidomide, 25 patients (30.1%) of the whole cohort had no RBC-TD. Although off-label, commencing disease directed treatment at that time reflects daily clinical practice of not waiting for a patient with MDS to become RBC-transfusion dependent. Whether this practice will alter the natural course of the disease and has an impact on long-term outcome is not known, as is the optimal time of starting therapy. However, interim analyses of the SINTRA-REV trial (ClinicalTrials.gov Identifier: NCT01243476) in non-TD LR MDS del(5q) patients suggest that early treatment with lenalidomide at low doses (5 mg) prolongs the time to and decreases the risk of TD with cytogenetic responses.7 This is supported by our data—although not corrected for disease duration and risk stratification—as patients with no RBC transfusions during the first cycle of treatment with lenalidomide had a significant improvement of median OS (P = 0.014). Renal failure in this elderly population was the most prevalent condition and is possibly the explanation for the fact, that in only 21 patients (25.3%) the recommended lenalidomide dose was given without alterations. Diagnostic evaluation with BM analysis was done in about half of the patients who received 12 treatment cycles, in all other patients treatment with lenalidomide was continued when peripheral blood values were (near) normal without morphological BM or cytogenetic response assessment. Response assessment beyond peripheral blood values seems to be of particular importance, as deep genetic responses are possible and could potentially lead to a treatment-free remission. Clarification on when and how response assessment has to be done is necessary. And there is a clear need for defining patient and disease characteristics with the possibility of a TFI.8 Median OS is significantly longer in lenalidomide-treated patients with MDS and isolated del(5q) compared with patients with other entities of MDS. This is longer compared with the MDS-004 study, which allowed recruitment of all subgroups of patients with MDS and del(5q), including patients with additional chromosomal abnormalities and blasts in BM of up to 10%, but all these patients had RBC-TD, which is in contrast to the SLIM-Registry.6 Observation time in our registry was too short to comment on the long-term safety of lenalidomide and on the possible occurrence of secondary malignancies. There is also a clear need for defining a diagnostic and therapeutic approach after stopping lenalidomide treatment due to intolerance or resistance to the drug with disease progression. ACKNOWLEDGMENTS We thank Mrs Gaby Fahrni, Clinical Research Coordinator at the Clinical Trial Unit Hematology, Luzerner Kantonsspital, Switzerland, for her contributions to data management. Additionally, the authors thank all data managers of the participating study centers in Switzerland contributing to enter data into the SLIM-Registry. The SLIM-Registry is sponsored by the Clinical Trial Unit Hematology, Luzerner Kantonsspital, Luzern, which was funded by an unrestricted grant from Celgene Switzerland. AUTHORS CONTRIBUTIONS AR and JSG designed the clinical data management application, performed research, and contributed as well as analyzed patient data. AR wrote the article. HA and NP developed, validated, and approved the clinical data management application and analyzed data. All authors performed research, contributed patient data, reviewed the article, and approved it for submission. DISCLOSURES AR received advisory from Amgen, AOP OrphaSwiss, Celgene/BMS, Janssen, Novartis, Sobi, Takeda. HA received current employment Unidata Geodesign GmbH, Vienna, Austria. RB received from advisory board, travel grants Abbvie, AOP OrphaSwiss, Janssen, Novartis, Sobi, Taked. NB received funding from Alexion, Astellas, Celgene/BMS, Novartis, Roche, Sandoz, Servier, Takeda and consultancy honoraria from Amgen, Celgene/BMS, Janssen, Novartis, Roche: travel grants; Celgene/BMS, Novartis. NC received advisory board and consultancy honoraria from AbbVie, Amgen, AOP OrphaSwiss, Astra Zeneca, Celgene/BMS, Gilead, Incyte, Janssen, Novartis, Pfizer, Takeda. AE received advisory board from Abbvie, Jazz Pharmaceuticals, Teva. TL received consultancy honoraria from AbbVie, Amgen, BMS, Incyte, Janssen, Swedish Orphan Biovitrum AG; research funding from Celgene, Novartis; and travel grants from AbbVie, Amgen. NP received current employment from Unidata Geodesign GmbH, Vienna, Austria. KS received advisory board from Amgen, AOP OrphaSwiss, Celgene/BMS, Janssen, Novartis. AS received advisory board, consultancy honoraria, travel grants, educational grants from Amgen, Celgene/BMS, Incyte, Janssen, Novartis, Sanofi, Takeda. H.-P. S received travel grants from Amgen, Celgene/BMS. GS received advisory board, consultancy honoraria, travel grants, educational grants, research funding from Amgen, Celgene/BMS, Gilead, Janssen, Novartis. JSG received advisory board, consultancy honoraria from Amgen, AOP OrphaSwiss, Celgene/BMS, Janssen, Novartis, Sobi, Takeda. The remaining authors have no conflicts of interest to disclose. SOURCES OF FUNDING Work at the Swiss Lenalidomide in MDS del(5q) (SLIM)—Registry was sponsored by Clinical Trial Unit Hematology, Luzerner Kantonsspital, Switzerland, which was funded by an unrestricted grant of Celgene Switzerland.

S166: MAGROLIMAB IN COMBINATION WITH AZACITIDINE FOR PATIENTS WITH UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROMES (HR MDS): 5F9005 PHASE 1B STUDY RESULTS

Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal overexpressed on cancer cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine (AZA) in the upregulation of “eat me” signals. A high unmet need exists to build on current standard-of-care AZA frontline therapy to increase efficacy while maintaining a tolerable safety profile in patients (pts) with HR MDS. Aims: To report the final safety/tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in pts with untreated HR MDS (NCT03248479). Methods: Pts with previously untreated intermediate, high, or very high–risk MDS per the Revised International Prognostic Scoring System (IPSS-R) received magrolimab IV as a priming dose (1 mg/kg) followed by ramp-up to a 30-mg/kg QW or Q2W maintenance dose. AZA 75 mg/m2 was administered IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: A total of 95 pts (median age, 69 y [range, 28-91 y]) were treated. IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21% of pts. MDS was therapy related in 22% of pts; 26% had a TP53 mutation, and 62% had poor-risk cytogenetics. Median number of cycles was 6 (range, 1-27). The most common treatment-emergent adverse events (TEAEs) included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (44%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and white blood cell count decreased (30%). Six pts discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline (BL) at first postdose sample was −0.7 g/dL (range, −3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%, with 31% of OR-evaluable pts with abnormal cytogenetics at BL having cytogenetic CR. Median time to first OR, duration of CR (DCR), duration of OR, and progression-free survival (PFS) were 1.9, 11.1, 9.8, and 11.6 mo. Overall survival (OS) rates at 12 and 24 mo were 75% and 52%; median OS was not reached (NR) with 17.1 mo of follow-up (figure). In pts evaluated with sequential whole-exome sequencing with a variant allele frequency (VAF) cutoff of 5%, 3 of 3 pts with TP53 mutation who achieved CR had TP53 VAF <5% by cycle 5 day 1. Favorable outcomes were observed both in pts with TP53 mutation (CR rate, 40%; median OS, 16.3 mo) and wild-type TP53 (CR rate, 31%; median OS, NR) (table). Table. - Outcomes in patients with previously untreated HR MDS treated with magrolimab + AZA Outcome All patients N=95 a Wild-type TP53 n=61 TP53 mutation n=25 OR rate, % b 75 79 68 CR rate (95% CI), % 33 (23-43) 31 (20-44) 40 (21-61) Marrow CR rate, % 32 38 20 Stable disease with HI rate, % 11 10 8 Median DCR (95% CI), mo 11.1 (7.6-13.4) 12.9 (8.0-NR) 7.6 (3.1-13.4) Marrow CR rate with HI/any HI, % 17/59 20/61 12/56 Converted to red blood cell transfusion independence, % 14 10 24 Median PFS (95% CI), mo 11.6 (9.0-14.0) 11.8 (8.8-16.6) 11.0 (6.3-12.8) Median OS (95% CI), mo NR (16.3-NR) NR (21.3-NR) 16.3 (10.8-NR) a a 9 patients had missing TP53 status. b Defined as CR+PR + marrow CR+SD with HI.HI, hematologic improvement. Image:Summary/Conclusion: Magrolimab + AZA was well tolerated with promising efficacy in pts with untreated HR MDS, including those with TP53-mutated and –wild-type disease. A phase 3 trial of magrolimab/placebo + AZA (ENHANCE: NCT04313881) is ongoing.

Magrolimab in combination with azacitidine for untreated higher-risk myelodysplastic syndromes (HR-MDS): 5F9005 phase 1b study results.

7017 Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal overexpressed on cancer cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. Here we report final Phase 1b data in patients (pts) with untreated HR-MDS (NCT03248479). Methods: Pts with previously untreated intermediate-/high-/very high-risk MDS per IPSS-R received magrolimab IV as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg weekly or Q2W maintenance dose. AZA 75 mg/m2 was administered IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: 95 pts (median age 69 years [range 28, 91]) were treated. IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21%, respectively. MDS was therapy-related in 22%; 26% (n=25) had a TP53 mutation and 62% had poor-risk cytogenetics (27% complex). Median (range) number of cycles was 6 (1, 27). The most common TEAEs included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (44%). The most common Grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and WBC count decreased (30%). 6 pts discontinued treatment due to AEs. 60-day mortality was 2%. Median Hb change from baseline (BL) at first post-dose sample was –0.7 g/dL (range –3.1, +2.4). CR and objective response (OR) rates were 33% and 75% with 31% of evaluable OR pts with abnormal cytogenetics at BL having cytogenetic CR. Median time to first OR, duration of CR (DCR), duration of OR, and PFS were 1.9, 11.1, 9.8, and 11.6 mos. OS rates at 12 and 24 mos were 75% and 52%, respectively (median NR with 17.1 mos follow-up for OS). For patients evaluated with sequential WES with a VAF cutoff of 5%, 3 of 3 pts with TP53 mutation who achieved CR had TP53 VAF &lt;5% by C5D1. Favorable outcomes were observed in both TP53 mutant (40% CR, median OS 16.3 months) and wildtype pts (31% CR, median OS NR; Table). Conclusions: Magrolimab+AZA was well tolerated with promising efficacy in pts with untreated HR-MDS including those with TP53-mut and TP53-wt disease. A Phase 3 trial of magrolimab/placebo+AZA (ENHANCE: NCT04313881) is ongoing. Clinical trial information: NCT03248479. [Table: see text]

Alterations of choroidal circulation and vascular morphology in a patient with chronic myeloid leukemia before and after chemotherapy

BackgroundChronic myeloid leukemia (CML) is known to cause leukemic retinopathy due to leukemia cell invasion into the choroid; however, details of the circulatory dynamics and morphological changes in the choroid are unknown. The aim of this study was to present a case of leukemic retinopathy and examine choroidal circulatory and structural analyses using laser speckle flowgraphy (LSFG) and optical coherence tomography with a binarization method, respectively.Case presentationA 15-year-old male diagnosed with CML complained of blurred vision in his right eye. He was ophthalmologically diagnosed with leukemic retinopathy due to retinal hemorrhage in both eyes. Tyrosine kinase inhibitors achieved complete cytogenetic remission and resolution of retinal hemorrhages at 6 months after treatment. After the treatment, the best-corrected visual acuity had recovered from 0.1 to 1.2 oculus dexter (OD) and remained at 1.5 oculus sinister (OS). The rate of change in macular blood flow assessed by the mean blur rate on LSFG was 18.3% increase OD and 25.2% decrease OS 19 months after treatment. The central choroidal thickness showed 0.4 and 3.1% reductions OD and OS, respectively. The binarization technique demonstrated that the rate of luminal areas in choroidal areas exhibited 3.2% increase OD but 4.8% decrease OS.ConclusionChoroidal blood flow improved OD after treatment for CML, while it deteriorated OS, together with choroidal thinning due to reduction of luminal areas. The degrees of leukemia cell invasion into the choroidal tissue and tissue destruction might be different between the eyes in this case.

The Prognostic Implication of Adult Comorbidity Evaluation 27 Score in CML Patients on Tyrosine-Kinase Inhibitors

▪BackgroundThe advent of tyrosine kinase inhibitors (TKIs) has been dramatically improved outcome of Chronic Myeloid Leukemia (CML) patients. In TKI era, patients with CML has similar life expectancy compared to general population. Adult Comorbidity Evaluation 27 score (ACE-27) is a scoring system assessing the burden of co-morbidities reviewing 27 factors related to twelve organ systems, which has been extensively studied as a predictor of outcome in various medical settings. We hypothesized that ACE-27 has prognostic impact of newly diagnosed, chronic phase CML patients, treated TKI as a frontline therapy, in long-term outcome.MethodsWe reviewed patients with newly diagnosed chronic phase CML at the University of Texas MD Anderson Cancer Center from 2000 to 2014 who were enrolled in clinical trials. Patients who received TKIs (imatinib, dasatinib, nilotinib, or ponatinib) as a frontline therapy were included. Patient and disease characteristics, treatment details were collected prospectively, and further collected by retrospective chart review. ACE-27 score was calculated accordingly. We studied its association to treatment response, overall survival (OS) and event-free survival (EFS). Complete cytogenetic remission (CCyR) was defined as the absence of Philadelphia chromosome (Ph) by karyotyping. Major cytogenetic response (MCyR) is defined as less than 35% of metaphases with Ph chromosome. Major molecular response (MMR), molecular response (MR) 4.0, and MR4.5 are defined as BCR-ABL1 transcript ≤ 0.1%, ≤ 0.01%, and ≤ 0.0032% on the international scale, respectively.ResultsIn a total of 524 patients, median age was 49 (range 15-86) with 16% of patients over age 65. Median follow-up time was 98 months. 267 (51%) patients were on imatinib, compared to 21% on dasatinib, 20% on nilotinib and 8% on Ponatinib. ACE-27 score was 0, 1, 2, and 3, in 284 (54%), 164 (31%), 64 (12%), and 13 (2%) patients, respectively. Detailed patient characteristics were summarized in Table 1. Patients with ACE-27 2-3 were less likely to achieve CCyR, MMR, MR4 or MR4.5 compared with those with ACE-27 0-1 (p=.010)(table 2). For ACE-27 2-3 patients, odds ratio (OR) for achieving CCyR, MMR, MR4 and MR4.5 compared to ACE-27 0-1 patients were 0.39 (p=.003), 0.43(p=.005), 0.52(p=.012), 0.60(p=.046), respectively. Time to response in each remission was similar between ACE-27 0-1 and ACE-27 2-3 groups. Overall survival was worse in ACE-27 2,3 patients with median survival at 12.5 years compared to not reached in patients with ACE-27 0 or 1, or 0 and 1 (p<.0001) (Figure 1). Hazard ratio(HR) for death in ACE-27 2-3 was 9.7(5.3-17.4, p<.001) compared to ACE-27 0. After adjustment with age ≥65, gender, sokal score, type of TKIs, still ACE-27 2,3 showed significant worse survival compared to ACE-27 0 or ACE-27 0, 1 at HR 7.18(95% CI 3.8-13.6, p<.001), HR 6.7(3.9-11.7, p<.001), respectively. When stratified by TKI types, ACE-27 2-3 remains statistically significant worse outcome in patients, though analysis on ponatinib and dasatinib was limited due to small number. ACE-27 2-3 patients also showed inferior EFS in ACE-27 2-3 with median EFS at 6.3 years(p=.007), but not well separated between patients with score 0 and 1(Figure 2 right, p= .262). HR for event in ACE-27 2-3 group was 1.81 (95% CI 1.09-2.99, p=.022) compared to ACE-27 0 group. When patients with ACE-27 0 and 1 are grouped together, survival curve is well-separated between ACE 27 0-1 and ACE 2-3 patients (Figure 2, p= .003).ConclusionACE-27 score predicts outcome including overall survival and event-free survival well in chronic phase CML patients. Our study demonstrated that co-morbidities has significant impact on outcome of chronic phase CML on TKI treatment, and the potentials of ACE-27 as a part of prognostic instrument. [Display omitted] DisclosuresKantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding. Konopleva: Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; KisoJi: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Clearview Healthcare Partners: Consultancy; CareDx, Inc.: Consultancy; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Consultancy; Sager Strong Foundation: Other; Bristol-Myers Squibb Co.: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Daiichi Sankyo, Inc.: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Blueprint Medicines: Consultancy; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; ImmunoGen, Inc: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Plexxicon: Other, Research Funding. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Protagonist: Consultancy. Kadia: Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Jazz: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; Sanofi-Aventis: Consultancy; Ascentage: Other; Genfleet: Other; AstraZeneca: Other; Astellas: Other; BMS: Other: Grant/research support; Cellonkos: Other; Pulmotech: Other; Liberum: Consultancy; Novartis: Consultancy; Amgen: Other: Grant/research support. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding.

Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Introduction: Therapeutic options for relapsed/refractory (r/r) acute myeloid leukemia (AML) and hypomethylating agent (HMA) failure higher risk myelodysplastic syndrome (MDS) are limited with a median overall survival of < 6 months. Although chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B-cell malignancies, significant challenges exist in myeloid CAR development. PRGN-3006 UltraCAR-T are engineered using non-viral gene delivery to simultaneously express CD33 CAR, membrane bound IL-15 (mbIL15) and kill switch to be effective against AML with improved safety profile. UltraCAR-T cells are manufactured at medical center's cGMP facility using autologous T cells in < 48 hours without ex vivo expansion.Methods: A Phase 1/1b first-in-human dose escalation/dose expansion clinical trial (NCT03927261) of PRGN-3006 in adult pts with r/r AML, HMA failure higher risk MDS or chronic myelomonocytic leukemia (CMML) with ≥ 5% blasts. Pts who have relapsed post allogeneic stem cell transplant (SCT) are allowed if > 3 months out from transplant without evidence of active graft versus host disease (GvHD) and off immunosuppression for 6 weeks. Ps receive PRGN-3006 infusion without (Cohort 1) or with lymphodepletion (fludarabine 30mg/m 2 and cyclophosphamide 500mg/m 2 days -5 to -3; Cohort 2). Dose escalation of Cohorts 1 and 2 occur in parallel with initial clearance of Cohort 1 at each dose level (DL; Table 1).Results: As of July 25, 2021, data cut-off, 15 r/r AML pts have been treated in Cohort 1 (n=9) and Cohort 2 (n=6) with a median age of 60 years (33-77). Pts were heavily pre-treated with a median of 3 prior regimens (1-7), with 93% and 80% of pts being r/r to a HMA + venetoclax or intensive chemotherapy, respectively. Additionally, 40% of pts (n=6) had relapsed after SCT. 93% of pts were int/adv by ELN 2017 criteria (60% adverse). PRGN-3006 infusion at doses up to 1x10 6 cells/kg was well tolerated. There have been no deaths, DLTs, bone marrow aplasia, neurotoxicity or unexpected on-target/off-target toxicities related to PRGN-3006, and no use of the kill switch to date. One incidence of grade 2 GvHD was observed in a post-SCT patient (Cohort 2) on day 31, which resolved completely with corticosteroid therapy, and notably this patient responded to therapy. Cytokine release syndrome (CRS) occurred in 47% of pts (n=7; G1 in 5 pts) with only 1 transient grade 3 event (DL 1, Cohort 1) that resolved in < 24 hours with tocilizumab and dexamethasone. Median onset to maximum CRS was 11 days (range 4-15 days). Peak CRP and ferritin levels occurred at a median of days 8 and 9, respectively. No significant increase in plasma levels of inflammatory cytokines, including IL-6 and TNFa, was observed post treatment. The plasma levels of IL-15 did not increase with treatment confirming mbIL15 is not shed.In Cohort 1, dose escalation through DL3 has been completed. Dose-dependent expansion of PRGN-3006 was observed in all patients with mean peak copy numbers following DL1, DL2 and DL3 in peripheral blood at approximately 600, 9,700 and 28,000 copies/µg DNA, respectively, with persistence up to 7 months post-infusion in a pt with stable disease/blast reduction. No objective responses in cohort 1 have been observed to date.In Cohort 2, dose escalation through DL2 has been completed. Expansion of PRGN-3006 was higher in Cohort 2 compared to Cohort 1 with mean peak copy numbers following DL1 and DL2 in peripheral blood at approximately 11,000 and 120,000 copies/µg DNA, respectively, and persistence 3+ months post-infusion. The objective response rate (ORR) for Cohort 2 was 50% (3/6). At DL1, 1 of 3 pts obtained CRi and was bridged to SCT and remains in a measurable residual disease negative CR 6 months post-SCT. At DL2, 2 post-SCT relapse patients also obtained response: 1 CRh with complete cytogenetic remission and NGS clearance with a remission length of 2 months; and 1 PR that lasted 3 months in a patient with isolated extramedullary leukemia (Figure 1). All 3 responders remain alive at data cut-off (5-10 months).Conclusion: PRGN-3006 UltraCAR-T cells targeting CD33 have been well tolerated with low grade CRS. In the setting of mbIL15, there has been a dose-dependent robust expansion and durable persistence of PRGN-3006 with encouraging responses (50%) in patients treated following lymphodepletion. Enrollment is ongoing to DL4, and updated safety, efficacy, PK/PD and cytokine data to be presented. [Display omitted] DisclosuresSallman: AbbVie: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Talati: AbbVie: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau. Mishra: Novartis: Research Funding. Semnani: Precigen: Current Employment. Shah: Precigen: Current Employment, Current equity holder in publicly-traded company. Sabzevari: Precigen: Current Employment, Current equity holder in publicly-traded company; Compass Therapeutics: Current equity holder in publicly-traded company; Kinnate BioPharma: Membership on an entity's Board of Directors or advisory committees. Chakiath: Precigen: Current Employment. Lankford: Precigen: Current Employment, Current equity holder in publicly-traded company. Padron: Stemline: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; BMS: Research Funding; Taiho: Honoraria. Kuykendall: PharmaEssentia: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria. Komrokji: Geron: Consultancy; Taiho Oncology: 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; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau. Lancet: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Astellas: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy. Davila: Precigen: Research Funding. Bejanyan: Medexus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Avrobio (Spouse disclosure): Current equity holder in publicly-traded company; Magenta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen (Spouse disclosure): Consultancy, Membership on an entity's Board of Directors or advisory committees; Crispr Therapeutics (Spouse disclosure): Current equity holder in publicly-traded company; Teladoc Health (Spouse disclosure): Current equity holder in publicly-traded company; Organon (Spouse disclosure): Current equity holder in publicly-traded company; Kadmon (Spouse disclosure): Consultancy; Merck (Spouse disclosure): Current equity holder in publicly-traded company; American Well Corp (Spouse disclosure): Current equity holder in publicly-traded company; Thermo Fisher (Spouse disclosure): Current equity holder in publicly-traded company; Unitedhealth Group (Spouse disclosure): Current equity holder in publicly-traded company.

A Phase 2 Study of Futibatinib (TAS-120) in Patients with Myeloid or Lymphoid Neoplasms Harboring Fibroblast Growth Factor Receptor (FGFR) 1 Rearrangements

▪Background: Myeloid and lymphoid neoplasms (MLNs) with FGFR1 rearrangements are very rare but aggressive myeloproliferative malignancies, characterized by eosinophilia, lymphoid aggregates, and often myelofibrosis, and are recognized as a distinct disease group by the World Health Organization (WHO). In these neoplasms, FGFR1 rearrangements drive oncogenesis via dysregulation of downstream FGFR signaling. Allogenic hematological stem cell transplant (HSCT) is the recommended treatment for patients with FGFR1-rearranged MLNs, as these malignancies are often refractory to chemotherapy and tyrosine kinase inhibitors. Currently, no effective molecularly targeted treatments are available for these patients. Futibatinib is an oral, highly selective, irreversible inhibitor of FGFR1-4 that has shown antitumor activity against FGFR-deregulated tumors in preclinical experiments and in phase 1 studies. Recent results from a phase 2 study demonstrated the efficacy (42% objective response rate) and manageable safety of futibatinib in patients with FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In addition to cholangiocarcinoma, futibatinib treatment resulted in objective responses across tumor types harboring various FGFR aberrations in the phase 1 study. In a separate report, a patient with an FGFR1-driven myeloid neoplasm treated with futibatinib achieved complete hematologic and cytogenetic remission. Based on these data, a multicohort phase 2 study (NCT04189445) was designed to evaluate the efficacy and safety of futibatinib in patients with tumors harboring specific FGFR aberrations. Here, we describe the cohort of patients with MLNs harboring FGFR1 rearrangements.Study Design and Methods: In this global, open-label, multicohort phase 2 study, patients (≥18 years, with Eastern Cooperative Oncology Group performance status 0-1 and adequate organ function) will be enrolled into 1 of 3 cohorts by type of tumor and/or FGFR aberration. The cohort of patients with MLNs harboring FGFR1 rearrangements (as defined by WHO criteria) will include patients who are not candidates for HSCT or other therapies or who have disease progression following HSCT. Patients with clinically significant alterations in calcium-phosphorus homeostasis, ectopic mineralization/calcification, clinically significant retinal/corneal disorder, untreated or clinically/radiologically unstable brain metastases, or prior FGFR inhibitor treatment will be excluded. Approximately 20 patients will be enrolled in this cohort (sample size considerations based on differentiating a ≤10% historical control complete response [CR] rate with a 50% target CR rate with 95% power). Patients will receive futibatinib 20 mg once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criterion is met. The primary endpoint is CR rate. Secondary endpoints include objective response rate, CR with incomplete hematological recovery (CRi) rate, complete or partial cytogenetic response rate, and safety. Additional secondary endpoints are duration of CR, CR+CRi, and response; as well as event-free (leukemia presentation only), progression-free, relapse-free, and overall survival. The study was initiated in August 2020, and patient enrollment is ongoing. DisclosuresKiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Shitara: Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharm, Astellas Pharm, Medi Science, Eisai, Taiho Oncology: Research Funding; Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Novartis, Abbvie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim: Consultancy; Novartis, Abbvie, Yakult: Other: Speaker fee. Rosen: Taiho Oncology: Research Funding. Rha: Taiho Oncology, Inc.: Research Funding. He: Taiho Oncology, Inc.: Research Funding. Oh: Taiho Oncology, Inc.: Research Funding; AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok: Other: Grants or contracts from any entity; AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point: Other: Participation on a data safety monitoring board or advisory board. Melisi: Taiho Oncology, Inc.: Research Funding. Iwasa: Taiho Oncology, Inc.: Honoraria, Research Funding. Jiang: Taiho Oncology, Inc.: Research Funding. Liu: Taiho Oncology, Inc.: Current Employment. Takahashi: Taiho Oncology, Inc.: Current Employment. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Introduction: In spite of frontline response rates of 65-70% with AZA-VEN a majority of pts relapse, with only 35-40% alive at 3+ years. Outcomes in R/R AML are poor with median overall survival (mOS) 5 - 7months (m). Magro, an anti-CD47 antibody that blocks the “don't eat me signal” on macrophages, demonstrated efficacy with AZA in ND TP53wt (ORR: 63%, mOS 18.9m) and TP53mut AML (ORR 69%, mOS 12.9m). Combined blockade of CD47-SIRPa axis by Magro with AZA-VEN increased phagocytosis in AML cell lines in vitro regardless of TP53 mut status, and prolonged survival in vivo in both AZA-VEN sensitive and refractory AML PDXs (Jia Y et al, ASH 2021). We designed a phase Ib/II trial to evaluate this triplet (NCT04435691).Methods: Pts ≥18 years with ECOG PS ≤2 and WBC <15x10 9/L with adequate organ function were eligible. The initial phase Ib enrolled R/R AML pts only. Once the RP2D was established the Phase II enrolled pts in 3 arms - frontline, VEN-naïve R/R AML, and VEN-exposed R/R AML. The frontline cohort enrolled pts ≥75yrs, or pts with documented comorbidities conferring ineligibility for intensive therapy; or pts with adverse risk karyotype and/or TP53mut regardless of age/fitness.Pts received AZA 75 mg/m 2 on D1-7, VEN 400 mg (or equivalent per VEN label) on D1-28. Magro was dosed on cycle 1 D1, 4, 8, 11, 15, 22; weekly in cycle 2, and every 2 weeks in cycle 3+ (Fig. 1). At the end of the phase Ib (n=6 pts) no DLTs were noted and the Magro RP2D dose was established as 1 mg/kg on C1D1 and C1D4, 15 mg/kg on C1D8, and 30 mg/kg on C1D11 and subsequent doses.Primary objective were safety, maximum tolerated dose (MTD), and RP2D of the triplet. Secondary objectives included CR/CRi rate, DOR and OS. Responses were per ELN2017.Results: Between Aug 2020 and July 1 2021 38 pts with newly diagnosed (ND) (n=17), R/R VEN-naïve (n=8), and R/R-post-VEN failure (n=13) were enrolled. An additional 6 ND pts were enrolled after July 1. Pt characteristics are in Table 1. In the ND pts the median (med) age was 70 yrs (range 33 - 84). Most pts had high-risk features: 14 (82%) pts ELN adverse risk, 45% ECOG PS≥2, and 8 (47%) were TP53m (VAF med 32%, range 5 - 94%).Pts were evaluated for response and toxicity per intent to treat. 1 pt was still in cycle 1 and too early. The CR/CRi rate in the remaining ND pts was 94% (15/16) with a CR rate of 81% (Table 2). The 8-week mortality was 0. All pts achieved response after cycle 1. The med time to ANC recovery >0.5 and platelet recovery >50 among the CR/CRi pts was 28 (range 20 - 41) days and 24 (range 18- 41) days, respectively. Complete cytogenetic CR was achieved in 9 of 12 (75%) evaluable and MRD negativity by MFC <0.01% in 7 of 13 (55%) evaluable CR/CRi pts, with MRD monitoring ongoing. After a med follow-up of 3.4m, one of 17 frontline pts (a TP53 m pt) died after 7.6m from disease relapse, and one relapsed (the only MLFS pt) and is on alternate therapy (Fig 2). The other 15 pts continue on protocol. 7 of 8 ND pts with TP53m were evaluable (1 still in cycle 1) with a CR/CRi in 100% (7/7), CR in 86% pts (6/7), MRD negativity by MFC in 57% (4/7), CCyR in 3/4 evaluable pts, and 6/7 remain in remission.In R/R prior VEN-naïve AML the CR/CRi rate was 63% (5/8) with med OS not reached (range 1.2-9.7). In R/R prior VEN failure AML the CR/CRi rate was 27% (3/13) with med OS 3.1 (range 0.9-6.5; Table 2).Among all 38 pts the 4 wk and 8 wk mortality were 0 and 9.7% (n=4): these 4 deaths occurred in R/R pts. Frequent treatment-emergent non-hematologic adverse events regardless of attribution, of all grades included hypokalemia (58%), hypophosphatemia (55%), hyperbilirubinemia (53%), hyponatremia (53%) and sinus tachycardia (47%), and of Grade 3/4 included pneumonia (32%), febrile neutropenia (32%), hyperbilirubinemia (11%), elevated ALT (11), and skin infection (11%). Among 17 ND AML the med hemoglobin drop after magro 1 st dose was 1.1 g/dL (0.0 - 3.9) and after 2 nd dose was 0.8 g/dL (0.0 - 2.0). With close monitoring anemia was manageable with no SAEs, treatment interruptions or discontinuations due to anemia.5 pts, all ND AML, have transitioned to allo-SCT and are alive.Conclusion: The combination of AZA VEN Magro was safe. High CR/CRi (94%) rates and CR rates (81%) were noted in ND pts, with majority (82%) ELN adverse risk. ANC and platelet recovery were robust (<28 days) in ND pts likely due to the lack of cumulative neutropenia or thrombocytopenia with Magro. Anemia occurs early on and should be monitored. Enrollment is ongoing and pivotal registration approaches with this combination are planned. [Display omitted] DisclosuresDaver: Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Konopleva: KisoJi: Research Funding; Calithera: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding. Kadia: Amgen: Other: Grant/research support; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Astellas: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cellonkos: Other; Genfleet: Other; Ascentage: Other; Aglos: Consultancy. DiNardo: Novartis: Honoraria; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Pemmaraju: Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; DAVA Oncology: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; LFB Biotechnologies: Consultancy; Blueprint Medicines: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; AstraZeneca: Honoraria; Astex: Honoraria, Research Funding. Kantarjian: Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure:Venetoclax used in salvage setting. Magrolimab is not yet licensed for use in any indication.

BILATERAL CHYLOTHORAX AND ANASARCA CAUSED BY DASATINIB IN A PATIENT WITH CHRONIC MYELOGENOUS LEUKEMIA

TOPIC: Disorders of the Pleura TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dasatinib is one of the tyrosine kinase inhibitors that is used in the treatment for Philadelphia positive Chronic Myeloid Leukemia (CML). Pleural effusion can occur in 10% of patients on dasatinib, but chylothorax was rarely reported as a side effect of dasatinib (1,2). CASE PRESENTATION: A 52 year-old male with medical history of CML presented with shortness of breath over the past 4months. Patient was diagnosed with CML 10 years ago. Initially he was started on imatinib which he did not tolerate secondary to headache and he was switched to dasatinib 100mg daily which he tolerated for 5 years. Bone marrow biopsy showed complete cytogenetic remission in 6-months and he achieved major molecular remission. Physical exam was remarkable for reduced air entry to both lungs, abdominal ascites, and lower extremities pitting edema up to the groins. Basic labs were within normal limits. Chest X-ray showed bilateral pleural effusions and confluent bibasilar infiltrates. Computed topography of the chest showed large bilateral effusions with passive atelectasis in the lower lobes (figure-1A and 1B). CT scan of the abdomen and pelvis showed diffuse body edema in the lower abdomen extending to both lower extremities. Large right hydrocele and moderate left hydrocele were also noticed (figure-1C). Imaging guided thoracentesis was performed on the right side and 1900 ml of milky fluid was drained. Pleural fluid analysis showed total protein of 4.6 g/dL (serum total protein:7.3 g/dL), glucose of 97 mg/dL (serum glucose: 84 mg/dL), elevated lactate dehydrogenase (116 U/L), elevated triglyceride (485 mg/dL), and elevated cholesterol (83 mg/dL). Based on that, Diagnosis of chylothorax was made and dasatinib was discontinued. Patient was started on short course of diuretics and oral prednisone. After one month of dasatinib discontinuation, patients SOB improved significantly. Abdominal and lower extremities swelling has improved too. Repeated CXR showed improved bilateral pleural effusion (figure-1D). We kept patient off dasatinib with monthly check of BCR/ABL by PCR with plan to restart dasatinib at 50 mg daily or switching to another treatment if he relapses. DISCUSSION: Pleural effusion is a known side effect of dasatinib and few reports of unilateral chylothorax have been reported. Bilateral chylothorax and anasarca are very rare side effects of dasatinib. In most of the cases, discontinuation of dasatinib can improve symptoms. In a previous case report, 63 year-old female presented with right sided dasatinib induced chylothorax which totally resolved after switching dasatinib to nilotinib (2). In another case report, the 71 year-old patient presented with dasatinib induced chylothorax that initially resolved and then recurred after re-initiation of dasatininb (3). CONCLUSIONS: Bilateral chylothorax after dasatinib is very rare. Most cases resolve completely with dasatinib discontinuation. REFERENCE #1: Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. doi: 10.1056/NEJMoa1002315. Epub 2010 Jun 5. PMID: 20525995. REFERENCE #2: Al-Abcha A, Iftikhar MH, Abu Rous F, et al. Chylothorax: complication attributed to dasatinib use. BMJ Case Rep. 2019 Dec 16;12(12):e231653. doi: 10.1136/bcr-2019-231653. PMID: 31848139; PMCID: PMC6936595. REFERENCE #3: Chen B, Wu Z, Wang Q, et al. Dasatinib-induced chylothorax: report of a case and review of the literature. Invest New Drugs. 2020 Oct;38(5):1627-1632. doi: 10.1007/s10637-020-00932-3. Epub 2020 Apr 4. PMID: 32248338. DISCLOSURES: No relevant relationships by hamed daw, source=Web Response No relevant relationships by Christopher Haddad, source=Web Response No relevant relationships by Tariq Kewan, source=Web Response No relevant relationships by Talha Saleem, source=Web Response