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W4200155691 abstract "Leukemia: LeukemiaThe outcomes of patients with different forms of leukemia are improving drastically and rapidly. Recent examples include the progress in chronic lymphocytic leukemia (CLL) with the combination of Bruton tyrosine kinase (BTK) inhibitors and venetoclax;1 in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) with second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) and the bispecific antibody T-cell engager (BiTE) blinatumomab;2,3 and in pre-B ALL with chemotherapy and blinatumomab or with the antibody drug conjugate (ADC) inotuzumab. In acute myeloid leukemia (AML), nine agents have been approved by the FDA since 2017 for various indications.4 Using the novel agents per the FDA-approval indications (often as single agents and/or in the salvage setting) may not offer their best treatment value, because of the often-modest benefit and the high cost of the drugs. This is true, for instance, for single-agent blinatumomab or inotuzumab therapy in ALL salvage, and single-agent FLT3 inhibitors or IDH inhibitors in AML. Already, combined modality strategies of standard chemotherapy with the novel targeted therapies in salvage and frontline settings are demonstrating very favorable results. Herein is a summary of some of these breakthroughs, which are detailed in a more extensive review in the Cancer journal.4 And a word of caution—some of the strategies discussed are not yet confirmed (and may not be confirmed for years to come) in randomized trials. Yet the results are so positive that they beg the question as to whether the gold standard of randomized trials should still apply, or whether we can forgo them until combination schedules and outcomes, evaluated in single-arm trials with Bayesian designs and/or rigorous historical comparisons, are optimized, and until we establish more confidently the best regimens to take to randomized trials. This will be illustrated in the subsequent discussion. In 2021, the leukemias can be divided into three categories.4 The easy-to-cure leukemias (“easy leukemias”) are ones where the 5-10 year survival rates are above 70 percent: hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), core-binding factor (CBF) AML, chronic myeloid leukemia (CML), CLL, Ph-positive ALL, and ALL in younger patients (age <60 years). The intermediate-cure-potential leukemias (“intermediate leukemias”) are ones with 5-year survival rates of 40-70 percent: older ALL and younger non-APL/non-CBF AML (age <60 years), with particular cytogenetic-molecular exclusions. The difficult-to-cure leukemias (“difficult leukemias”) are ones with current 5-year survival rates <40 percent: older AML and particular AML subtypes (regardless of age) such as AML with complex karyotype, adverse mutations, TP53 mutations, mixed-lineage leukemia (MLL), therapy-related or secondary AML evolving from myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN). The Easy Leukemias Hairy Cell Leukemia The discovery of the efficacy of the adenosine nucleoside analogs cladribine (CDA) and pentostatin revolutionized the therapy and outcome of HCL, resulting in response rates of 90+ percent and 10-year survival rates of 70 percent. Because the relapse rate was still about 50 percent, and because the CD20 antibody rituximab was active in HCL, the two agents were given in a cladribine-rituximab sequential combination: CDA 5.6 mg/m2 intravenously (IV) over 2 hours daily x 5 (with growth factor support and antibiotics) followed a month later (once counts recovered) by rituximab 375 mg/m2 weekly x 8. This regimen resulted in a 10-year failure-free survival rate of 95 percent.5 Acute Promyelocytic Leukemia APL constitutes about 5 percent of AML cases. Following the discovery of the potent anti-APL efficacies of all-trans retinoic (ATRA), arsenic trioxide, and gemtuzumab ozogamicin (GO; ADC targeting CD33), the non-chemotherapy regimen of ATRA + arsenic trioxide (+/- GO) was investigated: ATRA 45 mg/m2 orally daily (in two divided doses) during induction, then, when in CR, 2 weeks on 2 weeks off for a total of 9 months; arsenic trioxide 0.15 mg/kg (about 10 mg fixed dose) daily during induction, then, when in CR, daily x 5 days per week for 4 weeks, every other month, x 4 courses (80 doses of maintenance; total 110 doses induction-maintenance). GO (6-9 mg/m2 x 1) is added in high-risk APL (WBC >10x109/L at presentation or during induction) and for persistent molecular disease 2-3 months into CR. This produced a CR rate of 90 percent and 5-year survival rate of 80+ percent.6 Randomized trials of the combination versus ATRA–idarubicin (standard of care) showed ATRA-arsenic trioxide to be superior.7,8 The ATRA-arsenic trioxide regimen is now standard of care in APL (with the addition of GO or idarubicin if high risk). Oral formulations of arsenicals are in development and will improve treatment delivery and convenience.9 Monitoring for PML-RARα measurable residual disease (MRD) in CR should be standard, so as to identify risk of relapse and trigger preemptive therapy.10 Core-Binding Factor Leukemias The subset of AML with the cytogenetic-molecular abnormalities of inversion 16 or translocation (16;16) [inv (16) (p13.1; q22), t (16;16) (p13.1; q22)] and translocation 8;21 [t (8;21) (q22; q22)] are the CBF AMLs, and constitute 10-15 percent of adult and 20-30 percent of pediatric AML cases. Their outcome improved with the implementation of two strategies: high-dose cytarabine and GO.11,12 Fludarabine/high-dose cytarabine regimens produced better results in retrospective analyses of CBF AML.13 In the MRC randomized trials, two courses of fludarabine/high-dose cytarabine/idarubicin followed by two courses of high-dose cytarabine (when tolerated) resulted in a 5-year survival rate of 95 percent.14 In a meta-analysis of five randomized trials, the addition of GO improved the 5-year survival in CBF AML from 50 percent to 75 percent (p<0.0001).12 At MD Anderson, the combination of fludarabine/high-dose cytarabine/GO (FLAG-GO) resulted in a 5-year survival rate of 80 percent in younger AML and 55 percent in older AML (>60 years of age).15 Persistent MRD in CBF AML is associated with worse outcome and warrants consideration of allogeneic stem cell transplantation (SCT) or additional therapies to eliminate MRD (e.g., hypomethylating agents with GO or venetoclax).16,17 Chronic Myeloid Leukemia Following the unraveling of the molecular pathophysiology of CML, the BCR-ABL1 TKIs were developed. The first, imatinib mesylate, transformed the treatment and prognosis of CML, resulting in 10-year survival rates of 75-80+ percent (all-cause mortality events), 90 percent if only CML- or treatment-associated mortality events were counted. Today, CML is “functionally” curable with optimal TKI therapy, meaning that patients can have a nearly normal life expectancy on therapy with imatinib or second-generation TKIs, and with salvage therapies including other second- or third-generation TKIs, allogeneic SCT, and additional salvage approaches.18 Five TKIs are approved by the FDA for the treatment of Ph-positive CML, four of them as frontline therapy: imatinib, dasatinib, nilotinib, and bosutinib. Ponatinib, a third-generation TKI, is approved in resistant disease with a T315I mutation, or post failure of at least two TKIs. The aims of therapy in CML are the normalization of survival and, if possible, achievement of a “treatment-free remission” (TFR) status. For normalization of survival, frontline therapy with imatinib, dasatinib, nilotinib, or bosutinib achieves the goal once patients have a complete cytogenetic response (CG CR), or its molecular equivalent (BCR-ABL1 transcripts <1 percent on the International Scale [IS] by PCR). Details of CML management with regard to monitoring response and side effects, dose schedules of TKIs in frontline and salvage settings, milestones that reflect response or resistance (and need to change TKI therapy), and indications for allogeneic SCT are described in other reviews.18-20 Achievement of a TFR is considered in younger patients to avoid lifetime therapy. Discontinuing TKI therapy after achieving deep molecular response (DMR; BCR-ABL1 transcripts [IS] <0.01%) for 2-3 years is associated with a TFR rate of 50-60 percent.21 Discontinuing TKIs after achieving DMR for 5+ years increases the TFR rate to 80+ percent.22 Novel third-generation TKIs are being developed in order to target T315I-mutated disease and to improve on efficacy and toxicity profiles beyond what is offered by ponatinib: asciminib, olverembatinib (HQP1351), vodobatinib (K0706), and others.23,24 Today, with optimal TKI-based therapy, CML is a functionally (normal life expectancy) and molecularly curable disease (TFR rate 30-40%). Future research involves strategies to increase the TFR rates and to reduce the toxicities and costs of TKIs. Chronic Lymphocytic Leukemia The medical textbooks may not have yet caught up with the reality that CLL is curable now.25 Recent data show that CLL may be potentially highly curable with finite durations of therapy (2 years?) involving combinations of BTK inhibitors and venetoclax (with or without additional CD20 antibodies).1 The first hint of the potential cure in CLL came from the long-term results of fludarabine-cyclophosphamide-rituximab (FCR) combination therapy. These showed that younger/FCR-fit patients with good prognostic features (mutated immunoglobulin heavy chain gene; no deletion of chromosome 17p or TP53 aberration) treated with FCR had a 10-year disease-free survival rate of 55-60 percent.26,27 Following a better understanding of the CLL pathophysiology, several classes of targeted drugs were developed, including ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor).28,29 The BTK inhibitors-venetoclax combination in finite durations of therapy might shatter the dogma of CLL incurability. Jain and colleagues reported on a single-arm Phase II trial in which 80 patients with CLL who were older (65+ years) or had adverse-risk features (deletion 17p, TP53-mutated, deletion 11q, or unmutated IGHV) received ibrutinib 420 mg daily x 3 months, followed by the addition of venetoclax (standard weekly ramp-up to 400 mg daily) for a total duration of 24 months. This produced a marrow undetectable-MRD remission (U-MRD) of 75 percent as best response; the 3-year PFS rate was 93 percent and 3-year survival rate 96 percent. Among 51 patients with U-MRD status who discontinued therapy (median time off therapy 12.4 months), 8 had MRD recurrence, and no patient had active disease progression (2 had Richter's transformation).1 A multicenter study used ibrutinib plus venetoclax for 1 year, followed by randomization to different arms based on MRD status.30 The marrow U-MRD rate was 68 percent. Other studies are evaluating combinations of other novel and less toxic BTK inhibitors such as acalabrutinib, zanubrutinib, pirtobrutinib (highly selective non-covalent BTK inhibitor; overcomes ibrutinib mutation-resistance) with venetoclax, with or without CD20 antibodies, both in frontline and relapsed CLL. Pirtobrutinib also may be effective in Richter's transformation.31-35 Ph-Positive ALL Before 2000, Ph-positive ALL in adults was almost incurable, except with allogeneic SCT (cure rate 35-40% in SCT-eligible patients). Fast forward to today (and following the experiences with Hyper-CVAD plus imatinib/dasatinib), and the experience since 2010 with Hyper-CVAD plus ponatinib suggests that Ph-positive ALL, historically the most treatment recalcitrant adult ALL subset, has now become highly curable. Among 86 patients treated (median age 47 years; range 39-61 years), the CR rate was 100 percent, the MRD negativity rate 99 percent, the PCR-negativity rate 84 percent, and the 6-year survival 76 percent. Less than 20 percent of patients (ones with BCR-ABL1 transcripts >0.1% 3+ months into therapy) underwent allogeneic SCT.36 The superiority of ponatinib over other TKIs in Ph-positive ALL has not been confirmed in randomized trials (although the superiority of dasatinib over imatinib was confirmed in a randomized pediatric ALL trial) but is supported by a meta-analysis and a propensity-matched score analysis.37,38 European colleagues explored early on the use of TKIs with minimal chemotherapy in older Ph-positive ALL and reported 5-year survival rates of 35-45 percent (still with reliance on SCT in first CR in 30-70% of patients). Following reports of the superiority of blinatumomab and inotuzumab over standard-of-care chemotherapy in refractory-relapsed Ph-positive ALL, Foa and colleagues treated 63 patients (median age 54 years; range 24-82 years) with dasatinib 140 mg daily (plus steroids during induction), and added blinatumomab 3 months into dasatinib therapy for 2-5 courses. The dasatinib-blinatumomab regimen resulted in a CR rate of 100 percent and a complete molecular response rate of 41 percent. At the 2021 EHA meeting, the updated result showed an estimated 3-year survival rate of about 77 percent and EFS rate of 71 percent. Relapses were observed in 9 patients (4 with CNS only relapse); 50 percent underwent allogeneic SCT.2 At MD Anderson, we now combine ponatinib and blinatumomab (starting in induction) with encouraging preliminary results.3 Among the first 20 newly diagnosed patients treated, CMRs were noted early in therapy, and all patients achieved CR. The estimated 2-year survival was 93 percent.3 Younger Acute Lymphoblastic Leukemia (Age 15-60 Years) Using regimens identical to pediatric ones (curative in 80-90% of children) resulted in a plateau survival rate of 50 percent in adult ALL (up to age 60 years) and of 20 percent or less in older ALL.39-41 These regimens combine a lot of cytotoxic agents given over long periods (2.5-3 years) and that leave the cured children with multiple long-term physical and mental issues. The pediatric regimens use intensified asparaginase-vincristine-steroids. Asparaginase may result in serious toxicities (liver dysfunction, thrombosis, pancreatitis, disseminated intravascular coagulopathy, hip necrosis), and these regimens are not well-tolerated in patients older than 40 years. The Hyper-CVAD regimen is a pediatric-inspired regimen that relegates asparaginase to later courses in CR (fewer side effects). It is more myelosuppressive than other pediatric-inspired regimens but can be delivered with an acceptable toxicity profile in adult ALL (up to 60 years) and, with modifications (mini-Hyper-CVD plus antibodies), in older ALL. The Hyper-CVAD regimen, developed in 1992, later incorporated CD20 antibodies (rituximab in 2000; ofatumumab in 2012), CD22/19 targeting antibodies (inotuzumab and blinatumomab starting in 2010), and BCR-ABL1 TKIs (imatinib in 2000, dasatinib in 2006, ponatinib in 2010) in the subset of Ph-positive ALL. The addition of rituximab to chemotherapy improved outcomes in Burkitt disease and in pre-B ALL, and this was confirmed in randomized trials. Replacing rituximab with ofatumumab in Hyper-CVAD further improved results in single-arm trials (compared with historical data). With Hyper-CVAD plus ofatumumab (given to patients up to age 60 years), the 4-year RFS rate was 60 percent and the 4-year survival rate was 68 percent. Among patients <40 years old, the 4-year survival rate was 74 percent.42 Topp and colleagues reported on the high efficacy of blinatumomab in refractory relapsed ALL.43 The efficacy of inotuzumab was demonstrated in pilot trials at MD Anderson.44,45 Randomized trials in refractory-relapsed ALL confirmed that the targeted agents were superior to standard-of-care intensive chemotherapy.46,47 This led to studies of combinations of the antibodies with mini-Hyper-CVD in refractory relapsed ALL and frontline older ALL, and, in 2015, of the antibody combinations with Hyper-CVAD (first blinatumomab, and later addition of inotuzumab) in patients up to age 60 years. In the first 38 patients treated, the CR rate was 100 percent, the MRD-negativity rate 97 percent, and the estimated 4-year survival rate 80 percent.48 Bassan and colleagues added blinatumomab after 3 and 6 courses of chemotherapy. Among 149 patients treated (median age 49 years; range 10-65 years), the CR rate was 90 percent. MRD negativity rate post chemotherapy consolidation was 73 percent and increased to 96 percent after the first cycle 1 of blinatumomab. Conversion from MRD-positive to negative status was noted in 20/23 patients (87%) post the first cycle of blinatumomab. The 12-month survival rate was 84 percent.49 The above and similar ongoing studies suggest that incorporating these novel therapies targeting CD19/20/22 into ALL chemotherapy regimens holds the promise of increasing the cure rates in adult ALL to levels close to pediatric ALL, and perhaps with much less chemotherapy. Monitoring MRD is standard of care, and MRD in CR leads to beneficial therapeutic interventions (blinatumomab, inotuzumab, allogeneic SCT). Next-generation sequencing (NGS) methods detect MRD levels as low as <10-6; these may predict better the risk of relapse and may allow adjusting the components and duration of therapy based on NGS MRD status in CR.50,51 The Intermediate Leukemias Acute Lymphoblastic Leukemia in Older Patients (>60 Years Old) In older ALL, intensive chemotherapy with Hyper-CVAD or other regimens results in good CR rates (70-80%), but is associated with severe toxicities, high mortality rates during induction and consolidation-maintenance, and low survival rates (3-year survival rate <20-25%). Adding inotuzumab and later sequential blinatumomab to low-intensity chemotherapy showed encouraging results in ALL salvage and older frontline ALL.52,53 Among 70 older, newly diagnosed patients (median age 68 years; range 60-81 years) treated, the mini-Hyper-CVD-inotuzumab-blinatumomab regimen resulted in a CR rate of 98 percent, MRD negativity rate of 96 percent, and 3-year survival of 54 percent, better than historical data with Hyper-CVAD in older ALL.53 Stelljes and colleagues used a pre-phase of low-intensity chemotherapy (cyclophosphamide-vincristine-steroids), followed by fractionated inotuzumab induction and two consolidations, followed by 5 courses of chemotherapy and 1 year of 6-mercaptopurine-methotrexate maintenance. Among 31 evaluable newly diagnosed older patients (median age 65 years; range 56-80 years), the CR/CRi rate was 100 percent, the MRD negativity rate 78 percent, and the 1-year survival 87 percent.54 Acute Myeloid Leukemia in Younger Patients (<60 years old) The cytarabine-anthracycline regimen (3 days of anthracycline and 7 days of standard-dose cytarabine; “3+7”) has been the accepted standard of care for 5 decades.55,56 It results in 5-year survival rates of 20-50 percent in younger AML. Several discoveries improved outcome (addition of high-dose cytarabine consolidations; optimization of anthracycline doses; adding GO to chemotherapy; improvements in allogeneic SCT; improvements in antibiotics, antifungals and supportive care).55,56 There is accumulating evidence of better chemotherapy than 3+7 (including high-dose cytarabine during induction; adding adenosine nucleoside analogs [fludarabine, cladribine] and GO). These are detailed in other AML reviews.55,56 More significant AML therapeutic breakthroughs occurred recently with the development of effective targeted therapies like venetoclax (BCL2 inhibitor), and FLT3 and IDH inhibitors, and adding them to standard chemotherapy. Since 2017, the FDA approved nine agents for various AML indications: two FLT3 inhibitors, gilteritinib and midostaurin; ivosidenib (IDH1 inhibitor); enasidenib (IDH2 inhibitor); venetoclax (BCL2 inhibitor) in combination with hypomethylating agents (HMAs) or low-dose cytarabine; GO; oral azacitidine (10-15% absorption; 14-day schedule monthly for AML maintenance); CPX-351; and glasdegib (hedgehog inhibitor). A 100 percent absorbable oral formulation of decitabine was approved for the treatment of MDS-CMML as an alternative to parenteral HMAs and could be used in AML. However, the real progress will not occur through simply using them in the FDA-approved indications (often as single agents in salvage or frontline therapy), but by combining them with chemotherapy or developing innovative combinations of multiple targeted therapies. At MD Anderson, the fludarabine/high-dose cytarabine/idarubicin (FAI, FLAG-IDA) and CLIA (cladribine replacing fludarabine) are frontline regimens in younger/fit AML, to which targeted therapies are added based on the AML characteristics. Venetoclax added to FLAG-IDA or CLIA in 60 newly diagnosed younger patients resulted in an overall response rate of 90+ percent, and an estimated 1-year survival of 78+ percent.57,58 FLT3 inhibitors added to chemotherapy improved results in FLT3-mutated AML. In the RATIFY randomized trial in younger (<60 years) newly diagnosed FLT3-mutated AML, the addition of midostaurin to 3+7 improved survival (estimated 5-year survival rate 50% versus 42%).59 In a single-arm trial of 79 patients with newly diagnosed AML (56% FLT3-mutated) treated with 3+7 and gilteritinib, the CR + CRi rate was 82 percent, and the 2-year survival rate 70 percent in the FLT3-mutated cohort.60 In another single-arm trial in 151 patients with newly diagnosed IDH-mutated AML, a combination of 3+7 and ivosidenib (60 patients with IDH1 mutation) or enasidenib (91 patients with IDH2 mutation) resulted in response rates of 74-77 percent and 1-year survival rates of 76-78 percent.61 Future improvements in outcomes of younger AML may happen through safe incorporation of chemotherapy with more than one targeted therapy (venetoclax, FLT3 or IDH inhibitors, GO) in simultaneous or sequential approaches. But this could produce significant myelosuppression and increase mortality. Effective antibodies targeting CD33, CD123, CD70, others (ADCs or BiTEs) to eradicate MRD would be of value. Menin inhibitors may improve outcome in MLL-AML, and perhaps in NPM1-mutated AML. The Difficult Leukemias Older AML Older patients with AML fit for intensive chemotherapy and with favorable-intermediate risk features may be treated with regimens outlined above. In a Phase I trial in 51 fit older patients (65+ years, or 60+ years with monosomal karyotype; median age 72 years) with newly diagnosed AML, the combination of attenuated intensive chemotherapy (idarubicin x 2 days, conventional-dose cytarabine x 5 days; “2+5”) and venetoclax (14 days; Days -6 to Day 7 of chemotherapy) resulted in a CR rate of 41 percent, an overall response rate (CR + CRi) of 72 percent, and a median survival of 11.2 months. In de novo AML, the CR rate was 68 percent, CR+CRi rate 97 percent, and median survival 31.3 months.62 The venetoclax “therapeutic window” (single agent for 1 week) showed it to reduce blasts by 50+ percent in 28 percent of patients. The “difficult AMLs” may represent 60-65+ percent of AMLs since the median age of patients is 68-70 years. Difficult-to-treat AML includes not only older/unfit AML, but also AML that historically responded poorly to intensive chemotherapy (therapy-related or secondary AML; complex karyotype; monosomies in chromosomes 5, 7, and 17; t(11q23); mutations involving TP53, ASXL1, RUNX1; and MECOM AML). Alternative strategies are needed in these patients. Progress in older/unfit patients resulted from understanding the role of epigenetics in cancer63,64 and the observed benefits of HMAs and low-dose cytarabine.65-67 Randomized trials of azacitidine and decitabine versus standards of care demonstrated the benefits of HMAs, which became a new standard of care in older/unfit AML.68,69 But their value was limited: median survival <12 months; CR rate 10-20 percent; overall response rate <40 percent. We first investigated low-intensity chemotherapy combining adenosine nucleoside analogs (clofarabine, cladribine), with cytarabine and HMAs. These resulted in better outcomes compared with historical single-agent HMAs: CR rate 60 percent and median survival was 12.5 months. In normal karyotype older/unfit AML, the median survival was 19.9 months and the 2-year survival rate 45 percent.70 When the anti-AML efficacy of venetoclax was discovered, it was combined with HMAs and with low-dose cytarabine in single-arm studies and later in randomized trials which confirmed the benefit of adding venetoclax to HMAs and low-dose cytarabine in newly diagnosed older/unfit AML. In the VIALE-A Phase III trial randomizing 431 newly diagnosed patients (75+ years or unfit for intensive chemotherapy) to azacitidine + venetoclax or azacitidine + placebo, the addition of venetoclax improved results: median survival 14.7 versus 9.6 months (p<0.001); CR+CRi 66.4 percent versus 28.3 percent (p<0.001); CR 29.7 percent versus 17.9 percent (p<0.001).71 Similar results were reported with the VIALE-C Phase III trial comparing low-dose cytarabine +/- venetoclax.72 A longer duration of decitabine induction (20 mg/m2 daily x 10) with venetoclax (21-28 days depending on the Day 21 marrow blasts) resulted in a CR rate of 66 percent, CR + CRi rate of 85 percent, and median survival of 18.1 months.73 To improve results further, we added venetoclax to the triplet nucleoside analogs regimen: cladribine/low-dose cytarabine/venetoclax alternating with azacitidine/venetoclax. Among 55 patients treated so far (median age 68 years; range 57-84 years), the CR rate was 78 percent, the CR + CRi rate 93 percent, and the 1-year survival rate 70 percent.74 Other important discoveries in AML include: 1) confirming the benefit of maintenance therapy in AML (e.g., oral azacitidine maintenance; FLT3 inhibitor maintenance);75 2) developing oral HMAs (100% absorbable oral decitabine-cedazuridine), which would facilitate treatment delivery in AML and MDS;76,77 3) the recent development of menin inhibitors and CD47/SIRP1 alpha targeting therapies; and 4) the potential value of NK cellular therapy. These may hopefully improve the outcomes in some of the worse AML subsets, MLL-AML and TP53-mutated AML. Among 31 evaluable patients treated with the menin inhibitor SNDX-5631 113-339 mg twice daily, the response rate was 48 percent, including 13/24 responses (54%) in refractory relapsed MLL-AML (Syndax update April 2021). Summary The existing and investigational therapies under development offer a very optimistic view regarding the potential cure of most leukemias soon. In 2021, HCL, APL, and CBF AML are associated with high cure rates with available therapies. CML is functionally and molecularly curable with BCR-ABL1 TKIs. CLL is potentially curable with recent regimens combining BTK inhibitors plus venetoclax for finite durations of therapy. The treatment paradigm in Ph-positive ALL may soon change from chemotherapy-TKIs to non-chemotherapy regimens of dasatinib/ponatinib plus blinatumomab. Combinations of chemotherapy and CD19/20/22 antibodies are showing high survival rates in both adult and older ALL. Adding targeted therapies to standard intensive chemotherapy and low-intensity therapies is improving the results steadily in AML. HAGOP KANTARJIAN, MD, is Professor and Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, where he is also the Samsung Distinguished Leukemia Chair in Cancer Medicine.Hagop Kantarjian, MD: Hagop Kantarjian, MDArticle References Online You can explore all the references for this article online at https://bit.ly/3qtYryg." @default.
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