Treatment Of Chronic Myelomonocytic Leukemia Research Articles

Development of Novel Protein-Drug Conjugates for the Treatment of Chronic Myelomonocytic Leukemia

Introduction: Chronic myelomonocytic leukemia (CMML) is a myeloid stem cell neoplasm with few effective therapies and poor prognosis. We have developed CCL2-drug conjugates that specifically bind, internalize and eliminate cells of the disease clone via inhibition of the key metabolic enzyme NAMPT. CCL2 is a chemokine which binds CCR2, a receptor expressed predominantly on the classical monocytes canonically expanded in CMML, while CMML stem and progenitors display ~100-fold higher CCR2 expression compared with healthy equivalents ( Ferrall-Fairbanks et al, Blood Cancer Discov 2022 3(6):536-553). CCL2-NAMPTi conjugates thus represent an attractive and novel strategy, co-opting both lineage specificity and therapeutic window to deliver payload drugs for efficient and targeted cell killing. Methods: Four NAMPTi warheads were made in adaptable seven-step synthetic route and covalently conjugated to human CCL2 though TGase. We screened the range of CCL2-NAMPTi conjugates on CCR2-expressing cell lines (THP-1; MV411) for their ability to reduce NAD/NADH and induce cytotoxicity. The lead CCL2-NAMPTi conjugate was identified based on its ability to reduce NAD/NADH levels, induce cell death, and show impermeability when using the unconjugated warhead alone. Plasma stability studies confirmed conjugate stability in mouse and human plasma with no release of unconjugated active warhead. The lead compound was then tested on CD14+ cells isolated from CMML patient peripheral blood (PB); examining NAD/NADH levels, cell viability and induction of caspase 3/8. To better understand its specificity and target cell population, we conducted in vivo studies using fluorescently labelled CCL2 in wild type and CCR2 KO mice. Therapeutic effectiveness of the lead conjugate was evaluated by means of NAD/NADH reduction in THP1 subcutaneous models. Results: All CCL2-NAMPTi tested induced cell death in THP-1 cells (IC50 1.1-7.2 nM) following 72 hours incubation. The lead compound, MM015, effectively reduced NAD/NADH levels in CCR2+ cell lines (THP-1; MV411) 24-48 hours following treatment (IC 50 0.1-0.8 nM), with a corresponding decrease in cell viability at 72 and 96 hours (IC 50 1.1- 2.1 nM). No effect was observed on CCR2- cell lines (Jurkat; PC9). Specificity of the lead conjugate was confirmed by measuring NAD/NADH levels and cytotoxicity in presence of 100-fold excess of unconjugated CCL2. Efficacy studies on primary CMML PB samples confirmed that MM015 exposure specifically reduced NAD/NADH levels (n=6, IC 50 0.5-15 nM) and cell viability (n=6, IC 50 1.9-250 nM), and induced caspase 3/8 activation. Flow cytometry analysis of CMML PB confirmed CCR2 expression was largely restricted to monocytes and precursors, as compared with other immune cell subsets (n=6). Accordingly, efficacy measures in treated whole PB were exclusively seen in the CD14+ population, sparing lymphoid and other lineage cells, demonstrating ability of CCL2-NAMPTi to selectively target the CMML disease clone. In vivo experiments using fluorescently labelled CCL2 confirmed selective uptake of intravenously administered human CCL2 by CCR2+ cells within mouse blood, bone marrow and in THP-1 subcutaneous tumour cells. No uptake of fluorescently labelled CCL2 was observed in CCR2 KO mice, further confirming CCR2 specific uptake. Additionally, measurement of human CCL2 in CCR2 KO mouse peripheral blood by ELISA confirmed CCR2 dependent CCL2 uptake, 1 hour following intravenous administration. In vivo efficacy studies showed consistent reduction of NAD/NADH levels in xenografted tumor cells, and monocytic cells in the murine BM compartment, 24 hours following IV injection of MM015. Conclusion: We have developed a novel drug delivery strategy utilizing CCL2-NAMPTi conjugates to selectively target and eliminate key CMML cell populations. CCL2-NAMPTi can effectively reduce NAD levels and induce subsequent cell death in CCR2-expressing cell lines, primary CMML cells and in vivo models. This innovative approach holds therapeutic promise to address this major unmet clinical need.

Phase 1/2 Study of Pacritinib in Combination with Azacitidine in Chronic Myelomonocytic Leukemia

Introduction and preclinical rationale Treatment options for chronic myelomonocytic leukemia (CMML) are limited. Hypomethylating agents (HMAs) are the only approved therapies but are associated with unsatisfactory response rates and do not impact disease evolution (Merlevede Nat Comm 2016). JAK inhibition can reduce GM-CSF signaling, which contributes to CMML pathobiology; ruxolitinib has been clinically evaluated in CMML demonstrating promising, but insufficient clinical activity. Pacritinib is a JAK inhibitor that has a unique profile which suggests it may be uniquely well suited for the treatment of CMML, including targeting of CSF1R and IRAK1, both of which are upregulated in CMML and related diseases (Obba Autophagy 2015, Rhyasen Cancer Cell 2013). Additionally, pacritinib was recently shown to be a potent inhibitor of ACVR1 (Oh AJH 2023), potentially allowing for increased iron availability and improvement in anemia. Pacritinib has been evaluated preclinically in CMML primary samples and mouse models where it demonstrated significant, albeit heterogenous activity (Yoshimi Blood 2017). To enhance the activity of pacritinib in CMML, it was also evaluated in combination with azacitidine in GM-CSF hypersensitive cell lines and primary CMML cells where profound synergy was noted (Ma ASH 2015). Based on encouraging preclinical data, we hypothesize that the combination of pacritinib with azacitidine will be an effective treatment strategy in CMML patients. Methods In this phase 1/2 trial, we will evaluate the safety and efficacy of pacritinib and azacitidine in newly diagnosed or previously treated CMML. Patients must be JAK inhibitor and HMA naïve (≤1 cycle of HMA allowed). Phase 1 will follow a ‘3+3‘ dose de-escalation design and will enroll 6-12 patients. The primary objective of this phase is to determine the recommended phase 2 dose (RP2D) of pacritinib in combination with a fixed dose of azacitidine. Pacritinib will be administered at 200mg twice daily (with a lower dose of 100mg twice daily being explored in the case of dose limiting toxicity) in combination with azacitidine 75mg/m 2 for 7 days. Phase 2 will utilize a Simon's two stage design to assess the preliminary efficacy of pacritinib in combination with azacitidine at the RP2D. In the first stage, after treating 6 patients at the RP2D, there will be an interim response assessment as part of the phase 2 portion. If at least 4 among these 6 patients show a response, the trial will proceed to a second stage and enroll an additional 12 patients. Patients will be treated for 6 cycles of 28 days each with an interim bone marrow biopsy after cycle 3. The primary endpoint of the phase 1 portion is the recommended RP2D through the assessment of dose limiting toxicities and of the phase 2 portion is the overall response rate (ORR) by the end of cycle 6 as defined by a clinical benefit or greater by myelodysplastic syndrome/myeloproliferative neoplasm International Working Group response criteria (Savona 2015). Secondary endpoints include duration of response, disease free survival, overall survival, changes in MPN-SAF total symptom scores, palpable splenomegaly, and adverse events. Several correlative studies are planned as part of this clinical trial. Modulation of biomarkers of disease activity with treatment including GM-CSF dependent STAT5 phosphorylation, MAPK, and PI3K signaling will be analyzed. We will also evaluate changes in mutational and cytogenetic burden with treatment as well as at baseline to identify predictive biomarkers of response.

Lenzilumab in Addition to Azacitidine Improves Complete Response Rates in Chronic Myelomonocytic Leukemia

Introduction: Chronic myelomonocytic leukemia (CMML) is a rare cancer orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine that drives leukemic monocyte proliferation. Standard of care (SOC) for CMML treatment includes azacitidine (AZA), with a complete response (CR) rate of 16-21% 1,2. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M; ACTRN12621000223831) trial investigates novel CMML therapies directed by molecular profiling. Lenzilumab (LENZ; Humanigen, Inc., Short Hills, NJ) a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF. PREACH-M interim results show that LENZ/AZA improves hematologic parameters, decreases spleen size, and dampens pro-inflammatory responses in CMML with RAS-pathway mutations. This report details the objective clinical responses from an interim analysis of the first 11 subjects who completed at least three months LENZ/AZA treatment. Methods: PREACH-M is a Phase 2/3 non-randomized, uncontrolled, open-label trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML. Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS-pathway mutations ( NRAS, KRAS, CBL) receive 24 cycles (every 28 days) of AZA (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with only TET2 mutations receive the same AZA regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for an additional 24 months. The primary endpoint is the frequency of complete response (CR) or partial response (PR) during the first 12 cycles according to Savona Criteria. Secondary endpoints include responses according to modified 2006 International Working Group criteria, 2 year overall survival, and symptom improvement. Results: As of July 2023, 15 subjects were enrolled in the LENZ/AZA arm (8 females, 7 males with mean age 69; mean white cell count 21x10 9/L, mean Hb 121 g/L; mean platelet count, 74x10 9/L, mean blast count, 10.1%). Mutations included; CBL (47% of subjects), NRAS (27%), KRAS (47%), NRAS and KRAS (13%), and TET2 (93%). Subjects exhibited CPSS-MOL scores, of intermediate risk 1 (n=1), intermediate risk 2-3 (n=8), and high risk 4-6 (n=6). All the 11 evaluable subjects at 3 months responded to LENZ/AZA. CR was achieved within 3 cycles in 55% of subjects. Six of the subjects demonstrated CR including 2 with a high risk CPSS-MOL profile and 8 achieved either CR or complete marrow response (blasts<5%) within 12 months. One subject had a platelet response, 1 subject each had PR and stable disease with blasts <5%. CMML progression was absent and 1 subject became eligible for allogeneic transplant. These findings exceed historical CR rates for hypomethylating agents (16%; 95%CI, 12-21% 1 and 21%;13-29% 2). Self-reported symptom scores from the standardized MPN-SAFFS improved from baseline (mean of 22 vs 12, P=0.06). Fifteen grade 3 and 9 grade 4 adverse events were reported of which 2 were “probably” ascribed to both LENZ/AZA and 7 were “possibly” ascribed to LENZ. No unexpected adverse events were observed. Conclusion: Interim analysis of the PREACH-M trial demonstrated that GM-CSF neutralization with LENZ/AZA, for the treatment of CMML with RAS-pathway mutations resulted in 55% CR, achieved early in treatment, durability up to 18 months, thus far, and no unexpected serious adverse events. These data suggest CMML is driven by a non-redundant cytokine that responds to immunotherapy. 1. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study. Invest New Drugs 2022;40(5):1117-1124. DOI: 10.1007/s10637-022-01283-x. 2. Zheng X, Lv L, Li X, Jiang E. Efficacy and Safety of Hypomethylating Agents in Chronic Myelomonocytic Leukemia: A Single-Arm Meta-analysis. Glob Med Genet 2022;9(2):141-151. DOI: 10.1055/s-0042-1744157.

Venetoclax (VEN) Improves Response Rates but Not Survival in Patients with Chronic Myelomonocytic Leukemia (CMML) Treated with Hypomethylating Agents (HMA): A Multicenter, Propensity Score Analysis

Introduction HMAs are the only approved therapy for CMML. In order to improve response rates and survival, the addition of VEN has been utilized in both CMML and after blast transformation (CMML-BT) with conflicting results in small single center studies. To clarify the role of upfront HMA+VEN in CMML and CMML-BT, we performed a large multicenter analysis. Methods We included patients with HMA-naïve CMML and CMML-BT treated with combination HMA and VEN from 4 academic centers. The primary outcome was overall survival (OS) with secondary outcomes including overall response rate (ORR) by 2015 MDS/MPN IWG criteria for CMML and 2022 ELN criteria for CMML-BT. To better appreciate the benefit of adding VEN to HMA treatment, we also performed 1:1 propensity score matched (PSM) analysis of patients treated with HMA alone as upfront therapy for CMML or CMML-BT. Matching was based on age, sex, ECOG performance status, CPSS-Mol, blood counts, peripheral and bone marrow blasts. Results Eighty-nine patients were treated with frontline HMA+VEN, 51 CMML and 38 CMML-BT (5 had received HMA alone for prior CMML). The median age was 71 years, 70% were male, and 83% had ECOG 0-1. Among CMML patients, 55% had MP-CMML subtype, 65% had CMML-2 and 12%, 30%, 58% were CPSS-mol intermediate-1, intermediate-2 and high risk, respectively. In the entire cohort, ASXL1 (63%), TET2 (47%), SRSF2 (39%) and RUNX1 (27%) were the most commonly mutated genes and 55% of patients harbored a RAS mutation ( KRAS [20%], NRAS [18%], CBL [13%], NF1 [11%], PTPN11 [9%]). For HMA combination partner, 46 (52%) were treated with azacitidine, 35 (39%) with decitabine, and 8 (9%) with both during their VEN course. During a median follow-up time of 15.8 months (mos) 52 patients (58%) died: 23 (45%) with CMML and 29 (76%) with CMML-BT. Among CMML patients, the ORR was 90%, including complete remission (CR) in 22%, complete cytogenic remission (CCR) in 4%, optimal marrow response (CMR) in 50%, and partial marrow response (PMR) in 6%. The OS of CMML patients was 25.1 mo (95% CI 15.7 - NR). A PSM population of HMA patients matched to HMA+VEN treated patients showing similar baseline characteristics. ORR was significantly higher with HMA+VEN (95%) as compared those treated with HMA alone (46%), p < 0.001. However, there was no significant OS difference between HMA+VEN vs HMA alone (19.1 mos vs 19.1 mos, p = 0.85, Figure 1). For CMML-BT patients, the ORR of HMA+VEN was 81% including CR in 17%, CR with partial hematologic recover (CRh) in 3%, CR with incomplete hematologic recovery (CRi) in 28%, morphologic leukemia-free state (MLFS) in 22% and partial response (PR) in 11%. The OS of CMML-BT patients was 8 mos (95% CI 4.6 - 26.2). A PSM population of CMML-BT patients treated with HMA alone showed a significantly increased ORR with HMA+VEN (82% vs 40%, p = 0.039). However, there was no difference in OS (7.49 mos vs 9.26 mos, p = 0.83, Figure 2). Among HMA-VEN treated patients, achievement of a CR was associated with an improved OS in the CMML (HR 0.31, 95% CI 0.13 - 0.75) and CMML-BT (HR 0.37, 95% CI 0.19 - 0.74). No predictors of response were identified, including the presence of a RAS mutation. In terms of safety, 7 patients (7.9%) had a grade 3/4 (G3/4) neutropenic infection and 2 patients (2.2%) had a G3/4 hemorrhagic event while being treated with HMA+VEN. A total of 29 patients went on to receive allogeneic transplant (alloSCT): 22 (43%) with CMML and 7 (18%) with CMML-BT. CMML patients who underwent alloSCT after HMA+VEN were younger as compared to non-transplanted patients (64 vs 74 years, p < 0.0001), but had otherwise similar baseline characteristics including stage, CPSS-mol category and prevalence of RAS mutations. Similarly, CMML-BT patients bridged to alloSCT were younger (66 vs 74 years, p < 0.002) and had a better ECOG performance status (p = 0.047). Of patients who received alloSCT, 10 patients (34%) died, 5 with CMML and 5 with CMML-BT. The median OS after alloSCT was 26.7 mo. Conclusions Although the use of VEN with HMA in the upfront treatment of CMML and AML secondary to CMML results in higher response rates compared to HMA alone, this combination does not improve survival based on this multi-center PSM analysis. The current sample size of CMML-BT may limit detection of OS differences between treatment groups. The role of VEN to reduce blasts and serve as a bridge to alloSCT, particularly after HMA failure, requires further investigation in larger studies in both the CMML and CMML-BT populations.

Suppression of KRAS and CBL Mutations and Hematological Improvement By Lenzilumab and Azacitidine Treatment in Proliferative Chronic Myelomonocytic Leukemia

Introduction: Mutations in RAS-pathway genes ( NRAS, KRAS, CBL) are amongst the most common somatic mutations in cancer and historically resistant to most therapies. Targeted therapies that impact the RAS-pathway constitute a major unmet need in oncology. The proliferative form of chronic myelomonocytic leukemia (CMML) is commonly associated with RAS-pathway mutations and has a high propensity to develop into acute myeloid leukemia. In pre-clinical models, Lenzilumab (LENZ; Humanigen, Inc., Short Hills, NJ), a proprietary Humaneered ® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF, resulted in a reduction of colony numbers and viability of CMML cells, with the greatest sensitivity in cells possessing RAS-pathway ( NRAS/ KRAS/ CBL) mutations, suggesting benefit in the targeted treatment of CMML. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ, in addition to azacytidine (AZA), in CMML subjects with RAS-pathway mutations and high dose sodium ascorbate (ASC) and AZA in CMML subjects without RAS-pathway mutations. Interim data from 11 subjects with RAS-pathway ( NRAS/ KRAS/ CBL) mutations in PREACH-M receiving LENZ/AZA demonstrate reductions in circulating GM-CSF and CRP with 8 subjects achieving complete response or optimal marrow response. This report describes improvements in variant allele frequencies (VAF) for RAS-pathway mutations and hematologic improvements associated with LENZ/AZA treatment in CMML. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label trial in 72 subjects, aged at least 18 years, with newly diagnosed CMML based on the WHO 2016 criteria; and RAS-pathway mutations at a variant allele frequency ≥3%. Subjects received 24 cycles (every 28 days) of AZA (SC; 75 mg/m 2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles). Subjects without RAS-pathway mutations received the same AZA regimen and sodium ascorbate (IV; 30g for 7 days (15g for 1st dose only; 30g thereafter if no evidence of tumor lysis syndrome); PO; 1.1g on all other days). VAF was determined from bone marrow mononuclear cells using a 41-myeloid panel using Illumina Hi-Seq with a depth of 1000x performed on bone marrow aspirates obtained at baseline and Day 1 of treatment cycles 4, 7, and 12. Results: As of July 2023, 11 subjects completed at least 3 months of LENZ/AZA treatments and follow-up sequencing data were available for 10 subjects. Five of 10 subjects showed >10% decrease in VAF for at least one mutation detected at baseline, including 5 decreased alleles in the RAS-pathway ( KRAS, CBL) out of 22 total VAF mutation responses. CBL mutations showed the largest change with a decrease in >50% VAF in three subjects. Decreases in RAS-pathway clones by LENZ/AZA were durable at 6 months. No decreases in VAF for any mutations were observed in 2 evaluable subjects following ASC/AZA treatment. Following 3 months LENZ/AZA treatment, blood monocyte count improved from a baseline of 11.0 ± 6.0 x 10 9/L to 2.0 ± 1.0 x 10 9/L (p=0.030). Blast differential improved from 10.5 ± 5.0% to 4.0 ± 3.5% (p=0.038). Platelet count increased from 90.0 ± 50.0 x 10 9/L to 150.0 ± 60.0 x 10 9/L (p=0.010). Statistical improvements remained durable for at least 6 (n=6) and 12 (n=3) months. Hemoglobin concentration increased 100.0 ± 22.0 g/L to 115.0 ± 10.0 g/L at 3 months (p=NS, n=11) and progressively increased to 122.0 ± 10.0 g/L at 12 months (p=0.024, n=3). Spleen length decreased from 15.0 ± 4.0 cm to 13.0 ± 4.0 cm (p=0.03) and decreased further to 11.0 ± 2.0 cm in subjects who received 12 months of treatment (n=3). No evidence of disease progression or relapse was observed in any subject. Conclusion: In 11 evaluable subjects with proliferative CMML and RAS-pathway mutations, GM-CSF neutralization with LENZ in addition to AZA standard of care, resulted in significant decreases in the proportion of KRAS and CBL mutant leukemic cells, accompanied by clinically significant hematologic improvements and a reduction in splenomegaly. Lenzilumab may have efficacy in preventing outgrowth of RAS-pathway mutations, specifically KRAS and CBL, in the context of CMML and other myeloid malignancies.

Abstract CT085: A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial

Abstract Background: Chronic myelomonocytic leukemia (CMML) is a rare, aggressive cancer for which no targeted therapy exists. Standard of care (SOC) includes azacitidine (A), with complete and partial response (CR and PR) rates ranging between 10-17%. The pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role in stimulating leukemic monocyte proliferation. Lenzilumab (LENZ) is a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class specificity and affinity that neutralizes GM-CSF to prevent signaling through its receptor. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ in CMML (ACTRN12621000223831p) to improve outcomes beyond those afforded by SOC. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label precision medicine trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML; cytopenia (hemoglobin < 100 g/L, platelets < 100 × 109/L or absolute neutrophil count < 1.8 × 109/L): white blood cell count ≥ 13 × 109/L; as well as TET2 and/or RAS pathway mutations (NRAS, KRAS, CBL). Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS pathway mutations, with or without TET2 mutations, receive 24 cycles (28 days) of A (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with non-RAS pathway mutations receive the same A regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for 24 months for survival, disease status, and CMML-related therapy. The primary endpoint is the frequency of CR or PR at any time during the first 12 cycles according to Savona Criteria. Secondary endpoints include overall survival and progression-free survival at 2 years; proportion of subjects with clinical benefit at any point during the 24 cycles; impact on physical and functional capacity; social well-being according to Multidimensional Geriatric Assessment and quality of life; as well as hematological and non-hematologic safety. Results: As of December 31, 2022, eight subjects were treated with A and LENZ (5 females, mean age of 67 years; 3 males, mean age of 69 years); among them 6 were evaluable based on at least 3 months of follow-up. CR or objective responses were observed in all evaluable patients including 2 with high risk based on molecular profiling. 10 grade 3/4 Serious Adverse Events were observed of which 2 were assessed by the investigator as possibly related to LENZ. Conclusion: The ongoing PREACH-M trial evaluates GM-CSF neutralization with LENZ in addition to SOC, in the treatment of CMML with RAS pathway mutations. Citation Format: Devendra Hiwase, David Ross, Steven Lane, Agnes Yong, Kirsty Sharplin, David Yeung, Lisa Butler, Dale Chappell, Cameron Durrant, Timothy Hughes, Daniel Thomas. A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT085.

Reversible cardiomyopathy in a patient with chronic myelomonocytic leukemia treated with decitabine/cedazuridine: a case report

BackgroundHypomethylating agents (HMAs) have shown efficacy in the treatment of hematological malignancies and are indicated for the treatment of chronic myelomonocytic leukemia (CMML). While the HMA decitabine, in its intravenous formulation, has been used since 2006 for the treatment of CMML, use of its oral formulation has been limited by poor bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. The dose of intravenous decitabine is limited by toxicities such as cardiomyopathy and heart failure. Therefore, cedazuridine was developed as an inhibitor of cytidine deaminase. Cedazuridine decreases the first-pass metabolism of oral decitabine allowing therapeutic levels to be achieved at lower doses, and thus, the novel oral combination of cedazuridine with decitabine was developed. While cardiomyopathy and heart failure are well-established adverse effects associated with intravenous decitabine alone, there to our knowledge there have been no documented incidences of reversible cardiomyopathy in the literature or in patients who participated in the phase 2 and phase 3 clinical trials of oral decitabine-cedazuridine.CaseThis case study presents an 85 year-old Caucasian female with CMML who developed cardiomyopathy and heart failure with reduced ejection fraction after completing 5 cycles of therapy with decitabine/cedazuridine. Furthermore, her symptoms and cardiac function recovered upon discontinuation of the drug.ConclusionsWe present an occurrence of reversible cardiomyopathy in a patient who completed 5 cycles of decitabine/cedazuridine, an oral combination therapy developed to enhance oral bioavailability of decitabine thereby limiting its adverse effects. As the decitabine/cedazuridine combination therapy rises in popularity due to its convenient oral formulation, more trials are needed to understand the prevalence of cardiomyopathy with this drug and to discover preventative strategies for cardiotoxic effects.

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia.

Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML). The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia-free survival (LFS), and duration of response were evaluated with the Kaplan-Meier method. Patients were stratified on the basis of prior HMA exposure. The authors identified 21 patients with CMML (eight with HMA-naive CMML and 13 with HMA-failure CMML) and 33 patients with sAML (11 with HMA-naive sAML and 22 with HMA-failure sAML) treated with CLAD/LDAC/HMA-based regimens. The CMML cohort was enriched for high-risk features (proliferative type, elevated blasts, and RAS/MAPK mutations). The overall response rate was 33% in CMML (50% in HMA-naive CMML and 23% in HMA-failure CMML) and 48% in sAML (82% in HMA-naive sAML and 32% in HMA-failure sAML). The median OS was 14.4, 8.8, 42.9, and 2.9months for HMA-naive CMML, HMA-failure CMML, HMA-naive sAML, and HMA-failure sAML, respectively. The median LFS was 14.4 and 3.9months for HMA-naive CMML and HMA-failure CMML, respectively. CLAD/LDAC/HMA-based regimens are effective in a subset of patients with higher risk CMML and sAML arising from CMML who have not previously experienced HMA failure. These findings must be confirmed in prospective studies.

Efficacy and Safety of Ruxolitinib for Treatment of Symptomatic Chronic Myelomonocytic Leukemia (CMML): Results of a Multicenter Phase II Clinical Trial

Introduction CMML is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with poor overall survival (OS). Like primary myelofibrosis, a large subset of CMML patients suffer from disease-related symptoms and splenomegaly that contribute to morbidity. We have demonstrated that CMML is molecularly characterized by hematopoietic stem and progenitor cell hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). As the sentinel kinase required for GM-CSF signaling, JAK2 represents a rational therapeutic target in CMML and pharmacologic inhibition has demonstrated activity in preclinical models and in a phase I/II clinical trial. The overall response rate in that trial was 38% by MDS/MPN IWG criteria and 43% of patients (pts) with baseline splenomegaly achieved a spleen response by palpation. However, that clinical trial did not systematically or objectively measure symptom burden or radiographic splenomegaly. Here, we report results of our second phase II clinical trial with ruxolitinib for treatment of CMML objectively measuring spleen responses and symptom improvement. Methods This was a phase II prospective multicenter study. Key eligibility criteria included confirmed diagnosis of CMML and having either symptomatic splenomegaly and/or a myeloproliferative neoplasms symptom assessment form (MPN-SAF) total score (TSS) >17, ANC ≥ 250/ul, and platelets ≥35,000 u/l. Ruxolitinib was administered at 20 mg po BID at the previously identified RP2D. Dose adjustments/holding occurred for both hematological and non-hematological parameters. The primary endpoint was clinical benefit or better response per International Working Group (IWG) criteria for MDS/MPNs and symptom improvement was assessed using the MPN-SAF TSS. Pts were treated at least for 16 weeks if no clear progression and those deriving a clinical benefit could continue on study. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and the percentage of spleen volume reduction (SVR) was captured. Daily measurements of the MPN-SAF were performed for up to 17 weeks while on study. Results A total of 29 pts were enrolled at 4 centers (Moffitt, John Hopkins, Cleveland Clinic and Dana Farber) between September 2019 and June 2022. The median age was 74 (63-87) years. The majority were white (93%) and male (62%) consistent with the known demographics of CMML. Most pts had CMML-0 (62%) and proliferative CMML (69%) by the French American British group criteria. Fifty nine percent were high risk by the Mayo Clinic CMML risk model. Two patients had prior hypomethylating agent treatment and two had prior hydroxyurea. The most common somatic mutations at baseline were TET2 (79%), SRSF2 (68%) and ASXL1(48%). NRAS (21%), CBL (37%), and JAK2 (21%) were seen at higher proportions than previously reported likely due to study inclusion criteria. The median duration of follow up was 16 months and at the data cut off 8 pts remains on treatment. The median duration on treatment was 4 mo (.5-23 mo). Treatment-related adverse events and reasons for discontinuation are similar to that reported in the initial phase 1/2 study. The overall response rate by MDS/MPN IWG criteria was 17%: 10% (3) partial response and 7% (2) marrow response; 69% (20) had stable disease and 14% (4) were not yet evaluable. In addition, a clinical benefit was achieved in 66% of pts (19/29). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan and 10/20 (50%) had 10% or more SVR (Figure 1a). Fifty four percent of patients achieved MPN-SAF TSS >50% reduction at 60 days and all but four patients demonstrated an improvement in MPN-SAF TSS (Figure 1b). The estimated median overall survival was 24 months (95% CI 9-39). Conclusions Ruxoltinib demonstrated meaningful clinical activity in CMML patients with splenomegaly and/or high disease symptom burden. Two thirds of patients achieved clinical benefit, 33% had ≥ 35% SVR, and 54% had a reduction in TSS>50%. The overall survival compares favorably to historical data among higher risk CMML and the magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis. Collectively, our data suggests that ruxolitinib is a viable therapeutic for patients with symptomatic CMML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Hypomethylating Agents in Chronic Myelomonocytic Leukemia: A Single-Arm Meta-analysis.

Background Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with features of the myelodysplastic syndromes (MDSs) and myeloproliferative neoplasm presenting with peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia, while the abnormal DNA methylation plays a critical role in the pathogenesis of MDS, which is a disease of disordered differentiation. Recently, with the rapid development of molecular biology, hypomethylating agents (HMAs) for the treatment of MDS has gradually become a research focus. The objective of this study was to evaluate the benefits and risks of HMAs for patients with CMML. Materials and Methods PubMed, Embase, the Cochrane Library, and three Chinese databases were searched for studies published before November 2020 that used HMAs in CMML. Results The pooled objective response rate (ORR), complete response (CR), and partial response (PR) were 50.0, 21.0, and 2.0%, respectively. The proportion of patients with minor response (MR) was significantly higher for decitabine (DAC) than for azacitidine (AZA). There was no significant difference in hematologic improvement, ORR, CR, and PR rates between the DAC and AZA groups. Hematological toxicity included neutropenia grade 3/4 (14.0%), anemia grade 3/4 (17.0%), and thrombocytopenia grade 3/4 (22.0%). Conclusion This study showed that HMAs were effective and safe in the treatment of CMML, but large multicenter study would be needed to confirm the efficacy of HMAs for the treatment of CMML with different risk level and genetic abnormality, to support individualization treatment theoretically.

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from the Ascertain Phase 3 Study

Abstract text:Background/Introduction:Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML.Methods:We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.Results:Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT).Conclusions:In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients.

Azacitidine Treatment in Patients with Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia Type 2 and Acute Myeloid Leukemia According to their Cytogenetic Findings

Abstract Introduction: Azacitidine is one of the hypomethylating agents available for the treatment of elderly patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). It is also used as an appropriate treatment of chronic myelomonocytic leukemia (CMML) in the real life setting. As treatment of AML and CMML is not curative, and allogeneic stem cell transplantation (allo-SCT) remains traditionally the only option, significant clinical benefits by hypomethylating agents have been reported. According to the available data, 16% of subjects with MDS who received azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, while two-thirds of patients who required blood transfusions no longer needed them. Nevertheless, it can also be hepatotoxic in patients with severe liver impairment and extensive liver tumors. Aim: to summarize the effect of azacitidine treatment in patients in the light of their general condition, blood count parameters, toxicity (general and hematologic), as well as the presence of cytogenetic aberrations. Materials and Methods: Twenty-seven patients of which 15 patients with MDS, 9 patients with CMML and 3 patients with AML received azacitidine treatment. The blood count levels and toxicity were followed for a period of twelve months. Results: 22.2% of our patients (6 of 27) of different hematologic diagnoses showed genetic aberrations in their DNA. All they showed quick disease progression and fatal outcome, four of them also developed hematologic toxicity. The remaining 77.8% had no cytogenetic findings. Of all the cohort, 19.05% developed toxicity during the course of the treatment, 38% – decreased leucocyte levels, 14.3% – decreased thrombocyte levels and 18.2% – decreased hemoglobin level. The erythrocyte levels were not substantially influenced by the treatment. The majority of the patients sustained stable levels of red blood cells, as well as of platelets and hemoglobin without remarkable changes between month 0 and month 6 of the treatment. Conclusion: Our results showed, that the main disadvantage of azacitidine treatment in our patients were progressive leucopenia (in 10/27 patients or 37% of cases) and toxicity (8/27 or 29.6% of cases).

BIO-ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS ESTIMATION OF DECITABINE AND CEDAZURIDINE IN HUMAN PLASMA USING LC-MS/MS

Objective: The present work aimed to develop a novel, reliable and accurate Liquid Chromatography-Mass Spectrometry/Mass spectrometry (LC-MS/MS) method for the simultaneous quantification of Decitabine and Cedazuridine a combined medication used for the treatment of chronic myelomonocytic leukemia in human plasma. Methods: Talazoparib drug is used as an internal standard in the study. Both the analytes and internal standard were isolated from 100 ml plasma samples by liquid-liquid extraction and then chromatographed on Zorbax SB-CN (4.6 mm×75 mm, 3.5 µm) column with a mobile phase consisting of 0.1 % ammonium formate and methanol in the ratio of 65:45 (v/v) pumped at 0.5 ml/min. The method had a chromatographic total run time of 5 min. Results: The developed method gave a symmetric peak at a retention time of 1.7 min for Decitabine, 2.2 min for Cedazuridine, 3.5 min for Talazoparib and satisfied all the peak properties as per USP guidelines. The mass spectral characterization of separated analytes in the LC method was performed using a mass detector operated at Multiple Reaction Monitoring mode with precursor-to-product ion transitions at m/z of 229 to m/z of 114 as MH+ion for Decitabine, m/z of 269 to m/z of 118 as MH+ion for Cedazuridine. A very sensitive limit of detection of 0.3 ng/ml was observed and showed a calibration curve linear over the concentration range of LLOQ (lower limit of quantification) to 500 ng/ml. The other validation parameters were found to have acceptable accuracy, precision, linearity, and selectivity. The mean extraction concentration was acceptable and very high for both the analytes in HQC (high-quality control concentration), MQC (medium quality control concentration) and LLOQ levels. The peak area response ratio of Decitabine and Cedazuridine with the internal standard in freeze-thaw, short term and long term stability studies was found to be acceptable confirms that the method is stable. Conclusion: It can be concluded that the proposed method is specific, accurate, and precise and could be used for the simultaneous estimation of Decitabine and Cedazuridine in human plasma.

Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Median overall survival of this aggressive myeloid malignancy is only 2-3 years, with a 15-30% risk of acute leukemic transformation. The paucity of clinical trials specifically designed for CMML has made therapeutic management of CMML patients challenging. As a result, treatment paradigms for CMML patients are largely borrowed from MDS and MPN. The standard of care still relies on hydroxyurea, hypomethylating agents (HMA), and allogeneic stem cell transplantation, this latter option remaining the only potentially curative therapy. To date, approved drugs for CMML treatment are HMA, including azacitidine, decitabine, and more recently the oral combination of decitabine and cedazuridine. However, HMA treatment does not meaningfully alter the natural course of this disease. New treatment approaches for improving CMML-associated cytopenias or targeting the CMML malignant clone are emerging. More than 25 therapeutic agents are currently being evaluated in phase 1 or phase 2 clinical trials for CMML and other myeloid malignancies, often in combination with a HMA backbone. Several novel agents, such as sotatercept, ruxolitinib, lenzilumab, and tagraxofusp have shown promising clinical efficacy in CMML. Current evidence supports the idea that effective treatment in CMML will likely require combination therapy targeting multiple pathways, which emphasizes the need for additional new therapeutic options. This review focuses on recent therapeutic advances and innovative treatment strategies in CMML, including global and molecularly targeted approaches. We also discuss what may help to make progress in the design of rationally derived and disease-modifying therapies for CMML.

Diagnosis and treatment of chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic cells and is a complex of heterogeneous conditions with both myeloproliferative and myelodysplastic features. The diagnosis of CMML is made using morphologic criteria including monocyte-dominant leukocytosis, dysplastic changes, and increased blasts in the bone marrow. Recently, the identification of monocyte subtypes in peripheral blood using multiparameter flow cytometry has been actively studied. Chromosomal abnormalities are the basis of CMML risk stratification, and mutations in several genes including ASXL1 are known to be important not only for the diagnosis and treatment of this disease but also for predicting its prognosis. The standard treatment principles for CMML have not yet been clearly defined; however, hypomethylating agents are mainly considered the frontline therapy in most cases. Although allogeneic hematopoietic stem cell transplantation has limited applications owing to its toxicity, it still plays an important role as the only curative treatment option. Researchers are continuing to develop new drugs for CMML treatment and to prove their clinical usefulness. This review summarizes what is known to date on the diagnosis, treatment, and prognostic factors of CMML and presents future directions by analyzing recent research trends.

Contemporary Risk Stratification and Treatment of Chronic Myelomonocytic Leukemia.

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk-adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. IMPLICATIONS FOR PRACTICE: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high-risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.

Hypomethylating agents in the treatment of chronic myelomonocytic leukemia: a meta-analysis and systematic review

ABSTRACT Objectives The present meta-analysis was performed to evaluate the efficacy, toxicities of both hypomethylating agents (decitabine and azaciticine) in the treatment of CMML patients. Methods All available cohort studies of patients with CMML treated with decitabine and azacitidine were identified. The primary endpoints of this meta-analysis were response to hypomethylating agents. Pooled estimates of treatment response and drug-related adverse events were calculated using fixed or random effect models. Results Fourteen studies with 600 CMML patients (decitabine: n=196; azacitidine: n=404) were identified and included for meta-analysis. HMAs yielded a pooled ORR estimate of 43% (95% CI: 36%-50%) in patients with CMML. Patients received either azacitidine or decitabine exhibited comparable incidence of ORR (43% vs. 45%, P=0.810), while significantly higher incidence of mCR was observed in patients treated with decitabine (23% vs. 10%, P=0.000). Decitabine treatment was also associated with higher incidence of transfusion independence (42% vs. 20%, P=0.044). Both HMAs led to objective hematologic or non-hematologic AEs (27%-43%), while dosage modification/delay were more frequent in patients treated with azacitidine (81% vs. 67%, P=0.021). Conclusion This current study may provide preliminary data in evaluating the efficacy and safety of HMAs in patients with CMML. Decitabine and azacitidine are comparable effective and safe in treating CMML. However, it is necessary to point out that any comparison of decitabine and azacitidine with respect to clinical outcomes can only be done in the context of a randomized controlled trial.

慢性粒-单核细胞白血病诊断与治疗中国指南（2021年版）

慢性粒-单核细胞白血病诊断与治疗中国指南（2021年版）

Curcumol and FTY720 synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways.

Chronic myelomonocytic leukemia (CML) is a myeloid tumor characterized by MDS (myelodysplastic syndrome) and MPN (myeloproliferative neoplasms). Allogeneic hematopoietic stem cell transplantation, chemotherapy, interferon, and targeted therapy are the main treatment methods for CML. Tyrosine kinase inhibitors (TKIs) are also a treatment option, and patients are currently recommended to take these drugs throughout their lives to prevent CML recurrence. Therefore, there is a need to investigate and identify other potential chemotherapy drugs. Currently, research on CML treatment with a single drug has shown little progress. Fingolimod (FTY720), an FDA-approved drug used to treat relapsing multiple sclerosis, has also shown great potential in the treatment of lymphocytic leukemia. In our study, we find that FTY720 and curcumol have a significant inhibitory effect on K562 cells, K562/ADR cells, and CD34+ cells from CML patients. RNAseq data analysis shows that regulation of apoptosis and differentiation pathways are key pathways in this process. Besides, BCR/ABL-Jak2/STAT3 signaling, PI3K/Akt-Jnk signaling, and activation of BH3-only genes are involved in CML inhibition. In a K562 xenograft mouse model, therapy with curcumol and FTY720 led to significant inhibition of tumor growth and induction of apoptosis. To summarize, curcumol and FTY720 synergistically inhibit proliferation involved in differentiation and induce apoptosis in CML cells. Therefore, synergistic treatment with two drugs could be the next choice of treatment for CML.

Successful long-term treatment with azacitidine in patient with chronic myelomonocytic leukemia.

The purpose of this article was to present a case of successful long term treatment with azacitidine in patient with Chronic Myelomonocytic Leukemia (CMML) and discussing possible contributing factors for its long term efficacy. Data from our case were compared with similar data available in the literature. Effective treatment with azacitidine resulted in overall survival of 11 years 5 months and we showed that applying multiple cycles of treatment is feasible. Our patient received 71 cycles of treatment with total duration of 7 years and 3 months. Our report about a patient with CMML and a good clinical course revealed, that long term treatment with azacitidine is feasible in some patients. Initially low bone marrow blast count, a relatively small malignant CMML clone, reduction of spleen size and fast platelet response seemed to be factors determining long term response to treatment in our patient. More data on CMML treatment by Hypomethylating Agents and their analysis are needed in order to make firm conclusions.