Monoclonal antibodies (mAbs), bispecific T cell engagers (BiTEs) and antibody–drug conjugates (ADC) as well as immunotoxins are increasingly used for cancer immunotherapy [
1‐
4]. Cellular immunotherapeutic agents, including the chimeric antigen receptor-engineered T cell (CAR-T) therapy and NK cell therapy, are undergoing extensive clinical investigation and development [
5‐
14]. Small molecule inhibitors targeting cellular oncoproteins and enzymes such as BCR-ABL, JAK2, Bruton tyrosine kinase (BTK), FLT3, BCL-2, IDHs, have fundamentally transformed the landscape of cancer therapy from cytotoxic chemotherapy to biomarker-driven precision therapy [
15,
16]. Combination chemotherapy (chemo) regimens have been challenged by chemo-free targeted therapies in several major hematological malignancies. Many novel agents and regimens were reported, with the latest clinical trial data updated at the 2020 American Society of Hematology (ASH) Annual Meeting. Major therapeutic developments and updates for hematological malignancies reported at ASH 2020 meeting were discussed at the recent Winter Symposium and New York Oncology Forum from the Chinese American Hematologist and Oncologist Network (CAHON.org) and summarized in this review.
Update of MPN therapy from ASH 2020 annual meeting
Historically, therapeutic phlebotomy, hydroxyurea and interferon-alpha (IFN) were the main supportive care measures for treating myeloproliferative neoplasms (MPN). Ruxolitinib was the first drug approved by FDA to treat patients with intermediate or high-risk primary or secondary myelofibrosis (MF) and a subgroup of polycythemia vera (PV) patients who have inadequate response or intolerant to hydroxyurea [
73]. Two retrospective studies presented at the 2020 ASH annual meeting investigated the impacts of ruxolitinib dose alteration on first-line treatment outcomes at the real-world settings (Table
8). Abstract 3442 summarized data from 183 patients. This study reported that 65 patients initiated the treatment in the label-recommended doses, and 75 patients initiated the treatment in the modified doses due to various medical reasons [
74]. The investigators found that dose modifications occurred in nearly 1/3 of those patients, with the majority requiring a dose reduction. Abstract 2518 is a multinational medical record review on clinical outcomes of 135 patients with myelofibrosis who received ruxolitinib as the first-line treatment [
75]. Among the 135 MF patients, 99 received stable doses and 36 received modified doses. The data from both studies demonstrated that many patients started with non-standard ruxolitinib dose, either higher or lower than the recommended doses, were associated with lower responses, poorer survival outcomes and higher rates of discontinuation due to disease progression. It was also shown that relatively few patients received subsequent treatment after ruxolitinib discontinuation. These data highlighted a significant unmet need for developing newer and more effective MF treatment strategies
.Table 8
Selected studies for myeloproliferative neoplasm from 2020 ASH annual meeting
3442 | | Ruxolitinib | Retrospective | N/A |
2518 | | Ruxolitinib | Retrospective | N/A |
1250 | | Vidaza/Ruxolitinib | 1b | ISRCTN 16783472 |
54 | | Momelotinib | Extension Study | N/A |
3002 | | Navitoclax/Rux | III | NCT04472598 |
1255 | | Navitoclax/Rux | III | NCT04468984 |
52 | | Navitoclax/Rux | II | N/A |
483 | Daltro De Oliveira et al. [ 90] | Interferon-Alpha | N/A | N/A |
Inspired by the success of hypomethylating agents as a treatment component in managing relapse/refractory AML [
76], a phase 1b Phazar trial tested the safety and efficacy of azacitidine/ruxolitinib combination for MPN patients who were either in “accelerated phase”
(MPN-AP, 10–19% blasts) or in post-MPN AML phase (MPN-BP, ≥ 20% blasts). All those patients were ineligible to receive hematopoietic stem cell transplantation (HSCT) [
77]. A modified two-stage continual reassessment method with an expansion cohort at the maximum tolerated dose (MTD), was used to establish the MTD of ruxolitinib (dose levels 0, 1, 2 and 3 = 10, 15, 20 and 25 mg twice daily, respectively) in combination with a fixed azacitidine dose of 75 mg/m
2 subcutaneously for 7 days of a 28-day cycle. A formal response assessment would be recorded after 6 cycles. Clinical activity was evaluated over 12 months through assessment of bone marrow response after 3 and 6 treatment cycles, as well as of PFS, leukemia-free survival (LFS) and OS. There were 34 patients enrolled in this study, 20 evaluable for disease response. The data from this study demonstrated that the azacitidine/ruxolitinib combination was well tolerated in both MPN-AP and MPN-BP patients. The toxicities were comparable to the individual agent. Of the 20 evaluable patients, 10 (50%) achieved a PR or CR. The OS compares favorably with that of the historical cohorts, and clinically meaningful responses were achieved for transfusion independence. One patient was successfully bridged to HSCT.
Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the three hallmark features of MF [
78]. Previously conducted phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2) verified the feasibility and efficacy of MMB as the first-line or second-line treatment for intermediate- or high-risk MF patients [
79,
80]. The abstract 54 further evaluated the impacts of 10-year MMB exposure on those patients [
81,
82]. Of the 137 pts who have been enrolled in the long-term follow-up study after participating in S1 or S2 study, 105 patients remained on MMB with therapy duration ranging up to 10 years. The data showed that in both S1 and S2, OS and LFS were similar between treatment groups (stratified HR for OS of 0.99 in S1, 0.96 in S2). Overall, 40% of patients randomized to MMB in S1 achieved a splenic response at any time during the study. For patients who achieved transfusion independence (TI) at any time during the study, the median duration of TI response was not yet reached in S1 and was > 1 year in S2. These data demonstrated MMB’s potential ability to durably address the unmet needs of patients with intermediate-/high-risk MF. Fedratinib is another FDA-approved selective JAK2 inhibitor [
83]. Long-term safety data of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) from JAKARTA trial were also updated [
84].
Navitoclax is a novel BCL-2 inhibitor that demonstrated cell-killing activity in MPN-derived cell lines and primary specimen ex vivo [
85]. Abstracts 3002 (Transform-1) and 1255 (Ttransform-2) investigated the combination of navitoclax/ruxolitinib in treating naïve and refractory/relapsed (RR) MF, respectively [
86,
87]. Interestingly, abstract 52 evaluated the efficacy of adding navitoclax to ruxolitinib in treating RRMF patients who bear high-risk mutations (HRM) (ASXL1, SRSF2, EZH2, U2AF1 and IDH1/2) in a phase 2 study [
88]. In that study, a total of 34 patients continued ruxolitinib therapy while also starting on daily navitoclax at a dose of 50 mg, which was escalated to 300 mg based on the patient’s tolerability. Mutation analyses were performed at baseline, 12 weeks and 24 weeks. The data showed that clinical improvement at 24 weeks was independent of HRM mutations and number of mutated genes. Interestingly, the investigators observed a correlation between percentage change of inflammatory cytokines in serum and the change of spleen volume.
Life-long treatment represents a major burden for patients with chronic MPN. Interferon-alpha
(IFN) appears to be the only drug that can provide long-term complete hematological remission (CHR) after discontinuation in some patients [
89]. Abstract 483 presented a study that aimed to identify clinical and molecular factors associated with long-term CHR after IFN treatment discontinuation and to compare clinical outcome of patients who discontinued therapy, to patients who continued IFN treatment despite achieving a CHR [
90]. A total of 381 patients on IFN were enrolled in this study (PV = 171, ET = 169 and PMF = 34). JAK2V617F was the most frequent driver mutation (78.8% of patients), while
CALR and
MPL were mutated in 15.5% and 2.9%, respectively. After a median follow-up of 72.4 months [range 28.4 -119.7] from IFN initiation, 131 patients were still on IFN treatment, while 250 patients had discontinued therapy. No significant difference was observed between patients who discontinued and those who continued IFN in terms of MPN subtype, initial clinical, biological or molecular characteristics. OS (HR 0.23, 95%CI [0.5; 1.14],
p = 0.07) and EFS (HR 0.53, 95%CI [0.19; 1.45],
p = 0.217) were not significantly different between the two groups. This study showed that IFN discontinuation represents a safe strategy for MPN patients who achieved CHR and particularly for patients with a driver VAF lower than 10% at the time of discontinuation. Importantly, those relapsed patients did not develop IFN resistance.
Update of CML therapy from ASH 2020 annual meeting
Currently, four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, nilotinib and bosutinib, have been approved by FDA for the front-line treatment of chronic myeloid leukemia in chronic phase (CML CP) [
91]. While second-generation TKIs could produce faster and deeper responses and low rate of disease progression, they failed to improve the long-term OS when compared with imatinib. Thus, the NCCN and ELN guidelines still recommend imatinib for CMP CP with low-risk disease defined by Sokal score or the latest European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) score [
92‐
94].
The approval of bosutinib for front-line CML-CP was based on early results of BFORE trial [
95] (Table
9). The final five-year follow-up results of BFORE were presented at ASH 2020. At 5-year follow-up, first-line therapy with bosutinib continued to show superior efficacy than imatinib to induce earlier and deeper molecular responses. An improvement in molecular remission (MR) with bosutinib was demonstrated across Sokal risk groups, with the greatest benefit in Sokal high-risk patients. Long-term AEs were generally manageable and consistent with previously reported and known safety profiles. These results confirm the use of bosutinib as a standard of care in patients with newly diagnosed CML-CP [
96]. Among the second-generation TKIs, most clinicians select one of them, depending on the toxicity profile for front-line treatment of CML-CP, assuming equal efficacies. The Japanese Adult Leukemia Study Group (JALSG) should be applauded for conducting a prospective randomized phase 3 study to compare nilotinib
vs dasatinib in achieving MR4.5 at 18 months for newly diagnosed CMP-CP. Basically, consistent with common assumption, nilotinib and dasatinib are equally effective in achieving MR4.5 as well as in achieving complete cytogenetic remission (CCyR) and major molecular remission (MMR) in terms of both frequencies and times to achievement with similar continuity. Safety profiles from both drugs were also consistent with the known AEs [
97].
Table 9
Selected studies for CML therapy from 2020 ASH annual meeting
46 | | Bosutinib versus imatinib | III | NCT02130557 |
45 | | Nilotinib versus dasatinib | III | #UMIN000007909 |
632 | | Ponatinib | II | NCT02467270 |
650 | | Asciminib | I | NCT02081378 |
LBA-4 | | Asciminib versus bosutinib | III | NCT03106779 |
651 | | HQP1351 (Olverembatinib) | II | NCT03883087 NCT03883100 |
652 | | Vodobatinib | I | NCT02629692 |
Ponatinib is a third-generation TKI, and the first TKI to exhibit activity against CML with T315I mutation. Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program based on the phase II PACE trial with daily dose of 45 mg. One of the main concerns for ponatinib was arterial occlusive events (AOEs) that occurred in 31% of patients (26% serious) [
98]. The marketing of ponatinib was suspended per the request from FDA in 2013 due to the concern for AOEs, and in 2014, ponatinib resumed marketing with label changes to narrow the indication, to provide additional warnings and precautions about the risk of blood clots and severe narrowing of blood vessels, to revise recommendations about dosage and administration of ponatinib. FDA granted ponatinib full approval for the treatment of adult patients with CML and Ph + ALL with T315I mutation or for whom no other TKI therapy is indicated in 2016 based on updated PACE results [
99]. The OPTIC (NCT02467270) post-marketing study was started in 2015 to understand the optimal ponatinib dose with three starting doses (45 mg, 30 mg and 15 mg daily) in patients with CML CP. At the ASH 2020 meeting, Dr. Cortes presented the interim analysis of the OPTIC trial. With a median follow-up of 21 months, the maximum benefit/risk ratio, regardless of mutation status or number of prior TKIs, was observed in patients treated with a 45 mg starting dose, with a reduction to 15 mg upon achievement of response of ≤ 1% BCR-ABL IS (International Scale). Patients with the T315I mutation who initiated ponatinib at 45 mg experienced better response rates than those who initiated ponatinib at 30 mg or 15 mg starting doses [
100]. On 12/18/2020, FDA approved the supplemental new drug application for ponatinib to treat patients with CMP CP with resistance or intolerance to at least 2 prior kinase inhibitors. There was an updated label to include an optimized, response-based dosing regimen with a daily starting dose of 45 mg and, upon achieving ≤ 1% BCR-ABL1 IS, dose reduction to 15 mg to maximize benefit over the risk.
Asciminib is an allosteric inhibitor that binds to a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from the other approved TKIs. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant [
101]. In the Phase 1, dose-escalation study, asciminib was administered once or twice daily (at doses of 10–200 mg). The median follow-up was 14 months among patients with CML CP. Asciminib produced 92% complete hematologic remission (CHR); 54% CCyR, 48% durable MMR, including 57% MMR in patients deemed to have resistance to or unacceptable side effects from ponatinib, as well as 28% durable MMR in patients with a T315I mutation. Dose-limiting toxicities included asymptomatic elevations in the lipase level and clinical pancreatitis [
102].
At ASH 2020, Dr. Cortes presented the updated efficacy and safety results in patients with T315I mutation. A total of 52 patients with T315I mutation received asciminib 200 mg BID. Among evaluable patients not in MMR at baseline, 23/49 (46.9%) achieved MMR; the Kaplan–Meier-estimated rate of durable first MMR among patients who achieved MMR was 87% (95% CI, 68.4–100.0) at 96 weeks and remained unchanged until 144 weeks. By 24 weeks, 57.1% of ponatinib-naive patients and 28.6% of ponatinib-pretreated patients achieved MMR. Asciminib is a promising therapeutic option for patients with CML CP/AP with T315I mutation, including those for whom ponatinib treatment has failed [
103]. In a phase III randomized trial, patients who have failed two TKIs without T315I, V299L mutation were randomized to either bosutinib or asciminib. The efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib
vs bosutinib in patients with CML CP previously treated with ≥ 2 TKIs were presented as a late-breaking abstract (LBA 4) at ASH 2020 [
104]. In total, 233 patients with CML CP who had received at least 2 prior TKIs were randomized 2:1 to receive asciminib at 40 mg twice daily (
n = 157) or bosutinib at 500 mg once daily (
n = 76). The rate of CCyR at 24 weeks was 40.8% and 24.2% with asciminib and bosutinib, respectively, with a common risk difference of 17.3% (95% CI 3.62–31.0%). MMR rates were 25.5% with asciminib and 13.2% with bosutinib, for a difference of 12.2 percentage points (95% CI 2.19–22.3; 2-sided
p = 0.029). MR4 and MR4.5 at 24 weeks were also higher with asciminib at 10.8% and 8.9% vs 5.3% and 1.3%, respectively. Regarding safety, all-grade and grade 3 or higher AEs were similar between the two arms (89.7% and 50.6% with asciminib vs 96.1% and 60.5%, with bosutinib). ASCEMBL data demonstrated statistically significant superior efficacies with asciminib compared with bosutinib and a favorable safety profile, supporting the use of asciminib as a new treatment option in CML CP, particularly in patients with resistance or intolerance to at least 2 TKIs.
It has been controversial or unclear about the predictive values of additional chromosome changes and cancer-related gene or other gene mutations in addition to the t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chromosome changes were identified in less than 5% of newly diagnosed CML patients. There were conflicting reports about the prognostic impact of CVT in response to TKIs and the role of front-line treatment with imatinib or second-generation TKIs in patients with CVT. The Italian Campus CML, a network of Italian physicians involved in the management of CML patients, conducted a retrospective study on the role of CVT [
105]. CVT were identified in 112 (3.3%) patients from a whole population of 3,389 subjects with newly diagnosed CML CP. Ninety-eight out of 112 patients (87%) exhibited three-way translocations, with chromosome 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners. Four- and five-way translocations were identified in 13 and 1 patients, respectively. The subtype of CVT had an impact on response and long-term outcomes. Patients with CVT involving chromosome 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chromosome 10, 14, 15 or 17 (75.8%
vs 30.4%, respectively,
p = 0.001), higher frequency of stable deep molecular remission (DMR) (48.7%
vs 22.2%, respectively;
p = 0.04), regardless of the type of front line TKI and the ELTS score. Due to its retrospective nature, this study does not allow to define which therapy is for CML harboring CVT at diagnosis, but optimal responses treated with second-generation TKIs were statistically higher than that treated with imatinib.
The Australian CML group assessed the impact of genomic events in 160/210 newly diagnosed CML CP patients enrolled on their TIDEL II clinical trial. They identified a novel class of Ph-associated events, which were associated with the formation of the Ph chromosome. Both cancer-associated mutation and Ph-associated events were found in 16% (25 out of 160) patients, and 5 patients (3% of total patients) had both events; and 45 patients (28%) had at least 1 genomic event. Both cancer-related mutations and Ph-associated events at diagnosis were associated with inferior PFS and MR and increased risk to progress to advanced phase or development of a BCR-ABL1 kinase domain mutation. Through the univariate and multivariate modeling, cancer-related gene mutations, Ph-associated events and the ELTS score were independent predictors of failure-free survival (FFS), failure to achieve MMR and MR4. Despite a proactive strategy for TKI switch and a higher imatinib starting dose, the presence of cancer-related gene mutations or Ph-associated events conferred inferior outcomes [
106].
In addition, two promising third-generation TKIs were presented at ASH 2020. HQP1351 (Olverembatinib, Ascentage Pharma, China), an oral third-generation TKI with low affinity against other kinases, had demonstrated promising efficacies in the phase I trial for CML patients who have failed prior TKIs and/or acquired T315I mutation [
107]. HQP1351 was granted fast-track designation by the US FDA on May 7, 2020. The results of pivotal phase II trials were presented at the ASH 2020 meeting. HQP1351 was highly efficacious in heavily TKI-pretreated patients with T315I-mutation CML CP or CML AP and was well tolerated. In 41 evaluable CML CP patients who did not have a CCyR at baseline, 31 (75.6%) achieved MCyR, including 27 (65.9%) CCyR and 4 (9.8%) partial CyR (PCyR). Total 20 out of 41 (48.8%) evaluable patients achieved MMR. In the 23 evaluable CML AP patients without MCyR at baseline, 12 (52.2%) patients achieved MCyR, including 9 (39.1%) CCyR and 3 (13.1%) PCyR. A total of 6 out of 23 (26.1%) evaluable patients achieved MMR [
108]. The safety profile was similar to that observed in the phase I trial, and no new safety signal was observed.
Furthermore, vodobatinib, a novel third-generation TKI effective against wild-type and mutated BCR-ABL1 with limited off-target activity, was evaluated in a phase I multicenter dose-escalation study in CML patients who failed ≥ 3 TKIs or less (if not eligible for other approved third-generation TKIs) (NCT02629692) [
109]. The activity and safety of vodobatinib were evaluated in both ponatinib-treated and ponatinib-naïve CML CP patients. As of Jul 15, 2020, 31 CML CP patients received vodobatinib at doses of 12–240 mg. At the highest dose of 240 mg, two dose-limiting toxicities were reported including grade 3 dyspnea and grade 2 non-cardiac chest pain and grade 2 shortness of breath due to fluid retention. The recommended Phase II dose was 174 mg daily. The AE profiles in both ponatinib-treated or ponatinib-naïve patients were acceptable and expected. As for efficacies, MCyR was seen in 68% CML CP patients, with deepening of molecular responses over time; MMR was achieved in 38% ponatinib-treated population. Comparable and promising efficacy was noted in both ponatinib-treated (50% CCyR) and ponatinib-naive (67% CCyR) groups, meriting further study of vodobatinib as a potential new agent for treatment of previously treated CP-CML.
In summary, these studies presented at ASH 2020 meeting will likely shape the future landscape of clinical management of CML patients, particularly those with T315I mutation and/or highly refractory cases.