A tour of leukemia progress in 2025, viewed through the MD Anderson leukemia research lens

ABSTRACT

Advances in the prognostication, monitoring, and treatment of both the acute and chronic leukemias have led to drastically improved outcomes over the past 2 decades. With the advent of targeted therapies, including antibodies such as blinatumomab and inotuzumab and small molecule inhibitors, such as the BCR::ABL1 tyrosine kinase inhibitors, Bruton tyrosine kinase inhibitors, and venetoclax, the treatment landscape of leukemia has drastically changed, improving survival outcomes while relying less on overall chemotherapy intensity in many leukemia types. This progress has allowed the categorization of more leukemia types as favorable (i.e., chronic lymphocytic leukemia, younger acute lymphoblastic leukemia [patients younger than 60 years], and Philadelphia chromosome‐positive acute lymphoblastic leukemia) in addition to the traditional favorable subtypes of acute promyelocytic leukemia, core‐binding factor acute myelocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia. Advancements in the treatment of TP53‐mutated, MECOM‐rearranged, and treated secondary AML are still needed to improve outcomes in these adverse risk groups. The authors also review the recent progress in the treatment of the acute and chronic leukemias.

Short abstract

Significant advances in the pathophysiology, prognostication, monitoring, and treatment of both the acute and chronic leukemias have led to drastically improved outcomes over the past 2 decades.

Through the lens of remarkable therapeutic research and landmark discoveries, our view is that most (if not all) leukemias can be cured in our era.

INTRODUCTION

Deciphering the molecular pathophysiology of the leukemias has resulted in rapid therapeutic progress since 2000 in both the acute and chronic diseases. Progress in leukemia research and treatment and improvements in outcomes have been so rapid that reviews even as recent as 2018 and 2022 do not capture exciting and often revolutionary changes. ¹ , ² , ³ In the 1980s, neither of the two chronic leukemias, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL), were readily curable, except for a small subset of patients with CML who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Since 2000, with the discovery of the BCR::ABL1 tyrosine kinase inhibitors (TKIs), patients with Philadelphia chromosome (Ph)‐positive CML have a near‐normal life expectancy, and about 20%–50% may stop TKI therapy without recurrence of CML (treatment‐free remission [TFR]), essentially achieving a functional or molecular cure. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Whereas CLL is still reported to be incurable in the literature and by CLL experts, the discovery of the Bruton tyrosine kinase (BTK) inhibitors and the BCL2 inhibitor venetoclax, and their combination into regimens given for 2 years appears to result in molecular remissions in most patients, which are durable after discontinuing therapy. ⁹ , ¹⁰ , ¹¹ In acute lymphoblastic leukemia (ALL), highly active anti‐ALL antibodies targeting the clusters of differentiation (CD) CD19, CD20, and CD22 combined with chemotherapy in B‐cell ALL, and with the more potent BCR::ABL1 TKIs (blinatumomab plus dasatinib or ponatinib) in Ph‐positive ALL, are resulting in 4‐year overall survival (OS) rates ≥85%. In the subset of Ph‐positive ALL, these chemotherapy‐free regimens avoid the need for intensive chemotherapy or allogeneic HSCT, except in those with high‐risk disease (high initial white blood cell count [>70 × 10⁹/L]). ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ The discovery and incorporation of several effective, targeted therapies in acute myeloid leukemia (AML; venetoclax; inhibitors targeting fms‐like tyrosine kinase 3 [FLT3], isocitrate dehydrogenase 1/2 [IDH1]/IDH2, and menin) into standard chemotherapy regimens are improving AML outcomes. ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ This progress is highlighted in Table 1.

TABLE 1.

Leukemia progress in 2025.

Disease	Current/proposed future therapies a	Cure/5‐year to 10‐year survival, %
Hairy cell leukemia	Cladribine + rituximab	90
Acute promyelocytic leukemia	All‐trans retinoic acid + arsenic +/− GO	80–90
Core‐binding factor acute myeloid leukemia	FLAG and GO +/− IDA (FLAG‐GO +/− IDA)	80–90
Acute myeloid leukemia (AML), younger/fit patients	FLAG‐IDA + venetoclax; CLIA + venetoclax; FLT3 or IDH inhibitors if indicated; maintenance therapy with oral azacitidine/decitabine/HMAs with venetoclax or FLT3/IDH inhibitors; allogeneic HSCT in first CR when indicated	50 to ≥60
AML, older/unfit patients (also complex karyotype, TP53‐mutated, MECOM, others)	Low‐intensity triple nucleosides (cladribine + cytarabine + HMAs + venetoclax), triplet or quadruplet regimens with HMAs + venetoclax + addition of other targeted therapies, e.g. FLT3/IDH/menin inhibitors	30–40 (except TP53‐mutated, MECOM, treated secondary AML)
Acute lymphoblastic leukemia (ALL) patients younger than 60 years	Hyper‐CVAD + CD19/CD22/CD20‐targeted antibodies	≥70
ALL, patients aged 60 years and older	Mini‐hyper‐CVD + inotuzumab + blinatumomab/dose‐dense Mini‐hyper‐CVD + inotuzumab + blinatumomab followed by CAR T‐cell therapy in CR	50
Ph‐positive ALL	Hyper‐CVAD + ponatinib, ponatinib + blinatumomab	≥80
Chronic myeloid leukemia	BCR::ABL1 tyrosine kinase inhibitors (imatinib, dasatinib, bosutinib, nilotinib, asciminib, ponatinib), allogeneic HSCT, others (cytarabine, HMAs, hydroxyurea)	85–90
Chronic lymphocytic leukemia	Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) + venetoclax +/− CD20 antibodies	≥90
Myelodysplastic syndrome (higher risk)	Parenteral HMAs, oral HMAs + venetoclax, others	≥40

Abbreviations: +/−, with or without; CAR, chimeric antigen receptor; CLIA, cladribine, high‐dose cytarabine, and idarubicin; CR, complete remission; mini‐hyper‐CVD, dose‐reduced hyperfractionated cyclophosphamide, vincristine, and dexamethasone; FLAG, fludarabine, high‐dose cytarabine, and granulocyte‐colony–stimulating factor; FLT3, FMS‐like tyrosine kinase 3; GO, gemtuzumab ozogamicin; hyper‐CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone; HMAs, hypomethylating agents; HSCT, hematopoietic stem cell transplantation; IDA, idarubicin; IDH, isocitrate dehydrogenase.

^a For details of current and proposed future therapies, see the text.

The rapid therapeutic progress and the fact that leukemias are rare tumors requiring cumulative expertise may create a knowledge gap between specialized leukemia centers and community practice. Thus, the dissemination of knowledge concerning leukemias and the specialized details unique to disease subtypes are relevant. In this review, we update important discoveries and progress in leukemia research that have emerged since our 2018 and 2022 reviews. ² , ³

In 2018, we divided the leukemias into three categories, according to their expected 5‐year to 10‐year OS and potential cure rates (accounting for age and current therapies at the University of Texas MD Anderson Cancer Center [MD Anderson]): favorable (5‐year OS rate, >70%), intermediate (5‐year OS rate, 40%–70%), and unfavorable (5‐year OS rate, <40%). In the 1980s, the only intermediate leukemia was acute promyelocytic leukemia (APL; cure rate, 30%–40% because of the discovery of the efficacy of anthracyclines), the two chronic leukemias were incurable, and the two adult acute leukemias, AML and ALL, were curable at rates of 20%–30% with intensive chemotherapy. Today, 4 decades later, several leukemias have shifted into the favorable category. The favorable leukemias around 2010 were hairy cell leukemia (HCL), APL, core‐binding factor (CBF) AML, and CML. Since 2017, several intermediate leukemias have been reclassified as favorable: CLL, younger ALL (younger than 60 years), and Ph‐positive ALL. In addition, two unfavorable entities were reclassified into the intermediate category: older ALL and younger non‐APL/non‐CBF AML (defined as age younger than 60 years with cytogenetic‐molecular exclusions, such as TP53‐mutated AML). The unfavorable leukemias still include the AML subtypes of older patients, complex or adverse karyotype, TP53‐mutated, MECOM‐rearranged, treated secondary AML (TS‐AML; myelodysplastic syndrome [MDS] treated with hypomethylating agents [HMAs] or treated myeloproliferative neoplasm [MPN] that transformed to AML), and the related higher risk MDS. KMT2A‐rearranged AML/ALL and Ph‐positive (BCR::ABL1‐rearranged) AML may be reclassified in the near future from unfavorable to intermediate risk with optimized therapies containing best‐in‐class menin inhibitors and BCR::ABL1 inhibitors.

THE FAVORABLE LEUKEMIAS

Hairy cell leukemia

Observation, supportive care, splenectomy, and chemotherapy were the mainstays of therapy in HCL until 1983, when the anti‐HCL efficacy of interferon alpha was discovered by Quesada and colleagues. ³⁰ This discovery helped establish and stimulate the exploration of the role of immunotherapy in cancer. This treatment was later supplanted by the discovery of the efficacy of the adenosine nucleoside analogs cladribine (CDA) and pentostatin, which changed the outcome in HCL. ³¹ , ³² These therapies yielded high response rates (80%–100%) and 10‐year survival rates (70%), but 50% of patients experienced relapse after a median of 5–10 years.

After discovering the efficacy of rituximab (CD20 monoclonal antibody), ³³ we combined it sequentially with CDA: CDA 5.6 mg/m² intravenously over 2 hours daily for 5 days (with growth factor support and antibiotics) followed 1 month later (upon recovery of counts) by rituximab 375 mg/m² intravenously once weekly for 8 weeks. ³⁴ , ³⁵ This regimen resulted in a 10‐year event‐free survival (EFS) rate of 95% in newly diagnosed HCL (Figure 1). The results were confirmed in a randomized trial investigating a slightly modified regimen (simultaneous CDA and rituximab rather than sequential) versus CDA alone (rituximab administered after ≥6 months if measurable residual disease [MRD] was detected). ³⁶ The MRD‐negative complete remission (CR) rate was 97% versus 24% (p < .0001). After a median follow‐up of 96 months, the MRD‐negative rate was 94% versus 12%. The simultaneous regimen resulted in more mucositis than in our study, but it also may be more effective in HCL‐variant. ³⁷ Other strategies targeting BRAF mutations with BRAF inhibitors (e.g., vemurafenib) in combination with rituximab or obinutuzumab are also active. ³⁸ , ³⁹ In HCL refractory to these modalities (a rarity today), BTK inhibitors (e.g., ibrutinib), blinatumomab (bispecific T‐cell engager targeting CD19), CD20 bispecific T‐cell engagers, and inotuzumab (CD22 antibody–drug conjugate [ADC]) may help.

FIGURE 1.

Survival of patients with hairy cell leukemia in frontline, salvage, and variant HCL settings who received cladribine followed by rituximab (MD Anderson experience). All five deaths in the frontline setting were unrelated to disease or treatment (one patient died from old age [96 years], one died from suicide, two died from other cancers, and one died from an unknown cause). HCLv, hairy cell leukemia‐variant; yr, year.

Acute promyelocytic leukemia

APL constitutes about 5%–8% of AMLs and is characterized by the cytogenetic translocation between chromosomes 15 and 17—t(15;17)(q22;q12)—and the consequent PML::RARA fusion. ⁴⁰ , ⁴¹ The discovery of anthracyclines in the 1970s led to a cure rate of 30%–35%. ⁴² Adding cytarabine and maintenance with methotrexate and 6‐mercaptopurine modestly improved the cure rate to 40%–45%. Induction mortality from complications of disseminated intravascular coagulopathy was high (about 20%–30%). ⁴³ , ⁴⁴ A differentiation pattern into remission was described with intensive chemotherapy in 1985. ⁴⁵

The high anti‐APL differentiation efficacy of all‐trans retinoic acid (ATRA) was reported in 1988, and that of arsenicals was reported in 1997. ⁴⁶ , ⁴⁷ Combinations of ATRA or arsenic trioxide with anthracycline‐based regimens produced 5‐year OS rates ≥80%, which established the anthracycline‐ATRA regimen (ATRA + idarubicin [IDA]; AIDA) as a standard of care in 2012. ⁴⁸ Studies from China, India, and Iran investigated ATRA and intravenous arsenic trioxide as single‐agent therapies in frontline APL, with single‐agent arsenic trioxide producing 5‐year OS rates ≥60%. ⁴⁶ , ⁴⁹ , ⁵⁰ These studies suggested that arsenic trioxide was the single most active anti‐APL agent, followed by gemtuzumab ozogamicin (GO), ATRA, and anthracyclines. ⁵¹

In 2001, we investigated the nonchemotherapy regimen of ATRA + arsenic trioxide as salvage, then as frontline therapy (with GO 6–9 mg/m² × 1 added in high‐risk APL [white blood cells (WBCs) >10 × 10⁹/L at presentation or during induction] and for persistent molecular disease, that is PML::RARA positivity by polymerase chain reaction after 2–3 months in remission). Oral ATRA 45 mg/m² daily (in two divided doses) and intravenous arsenic trioxide 0.15 mg/kg (about 10 mg fixed dose) daily are given both during induction (usually for 3–4 weeks, then 1 week off to allow for count recovery). In CR, ATRA is given 2 weeks on and 2 weeks off for 9 months; arsenic trioxide is given daily for 5 days (omit weekends), weekly for 4 weeks, every other month for four additional courses (80 doses of maintenance; total, 110 doses of induction plus maintenance). This regimen resulted in a CR rate ≥90% and a 5‐year OS rate >90%. ⁵² , ⁵³ , ⁵⁴ Randomized trials and real‐world experience of ATRA and arsenic trioxide versus AIDA confirmed the superiority of ATRA + arsenic in both higher and lower risk APL. ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ It is now a standard of care in APL (with the addition of GO or IDA if high risk). Oral formulations of arsenicals are in development and will improve the convenience of treatment delivery in CR. ⁵⁹ , ⁶⁰ , ⁶¹ Monitoring for PML::RARA MRD in CR should be standard to direct preemptive therapy. ⁶²

Details about unique situations of APL therapy (never use granulocyte colony–stimulating factor; fluid retention/overload and pulmonary/multiorgan failure; cap dose of arsenic at 15–20 mg daily to avoid renal dysfunction; increased intracranial pressure with ATRA and management; central nervous system [CNS] prophylaxis; others) are detailed in other reviews. ⁶³ , ⁶⁴ FLT3‐internal tandem duplication/tyrosine kinase domain mutations are noted in 30%–40% of cases; they are associated with a high WBC count at diagnosis but have not required the addition of FLT3 inhibitors in frontline therapy. Relapse of APL is still highly curable with ATRA + arsenic trioxide for longer treatment durations, without or with autologous HSCT. ⁶⁵

Core‐binding factor leukemias

The CBF AMLs include AML with inversion 16 or translocation (16;16)—inv(16)(p13.1q22), t(16;16)(p13.1;q22)—and with translocation between chromosomes 8 and 21—t(8;21)(q22;q22). They constitute 10%–15% of adult AML and 25%–30% of pediatric AML. Eosinophilia and CD2 and/or CD7 expression may be present in AML with inv(16); CD19 may be expressed in AML with t(8;21). The 5‐year OS rates in CBF AML increased from 30%–40% to 50% with the addition of four courses of high‐dose cytarabine consolidation and increased to 75% with the addition of GO. ⁶⁶ , ⁶⁷ We reported that the fludarabine/high‐dose cytarabine (FLAG) regimens were better in CBF AML. ⁶⁸ In the Medical Research Council (MRC) trials, patients with CBF AML who completed two courses of FLAG/IDA followed by two courses of high‐dose cytarabine had a 5‐year OS rate of 95%. ⁶⁹ In a meta‐analysis, the addition of GO improved the 5‐year OS rate from 50% to 75% (p < .0001). ⁶⁷ Recent data from the AML MRC19 trial did not demonstrate a difference in outcomes with daunorubicin and cytarabine plus GO versus FLAG/IDA plus GO; therefore, in the context of administering GO, further intensification of chemotherapy did not appear to be beneficial. ⁷⁰ At MD Anderson, we investigated the combination of FLAG‐GO and reported 5‐year OS rates of 80% in younger patients and 55% in older patients (older than 60 years). ⁷¹ , ⁷² , ⁷³ Persistent MRD is associated with a worse outcome, ⁷⁴ , ⁷⁵ and positive MRD status after four to six courses of treatment requires consideration of allogeneic HSCT or additional therapy (e.g., HMAs with venetoclax). ⁷⁶ , ⁷⁷ Frequent mutations in CBF AML include FLT3, KIT and RAS, and these were associated with adverse outcomes in frontline therapy in some studies, but not with the FLAG‐GO regimen. Adding mutation‐guided, targeted therapies in MRD‐positive CR or in salvage might be beneficial (e.g., KIT inhibitors, such as dasatinib, quizartinib, midostaurin, or avapritinib if KIT‐mutated or FLT3 inhibitors if FLT3‐mutated). ⁷⁸ , ⁷⁹

Chronic myeloid leukemia

CML is defined by the causative cytogenetic abnormality known as the Philadelphia chromosome, involving a translocation between chromosomes 9 and 22—t(9;22)(q34;q11)—and the resulting gene fusion BCR::ABL1. ⁴ , ⁵ , ⁶ , ⁸⁰ , ⁸¹ Before discovery of the BCR::ABL1 TKIs, CML was treated with cytotoxic agents, such as hydroxyurea and busulfan (1960–1980s) and interferon alpha (since 1983). The median OS was 3–4 years with busulfan/hydroxyurea and 6–7 years with interferon. The 10‐year OS rate was <10%. However, patients who achieved a complete cytogenetic response on interferon (10%–30%) had a 10‐year OS rate ≥50%, suggesting that suppression of the BCR::ABL1‐associated molecular events improved CML outcome. ⁸² Improving and expanding the availability of allogeneic HSCT since the 1980s offered a potential cure to select eligible patients, with 10‐year OS rates of 40%–60%. ⁸⁰ , ⁸¹

Confirming the causal association between the BCR::ABL1 molecular events and the development of CML‐like disease in animal models led to the search for and discovery of the efficacy of the first BCR::ABL1 TKI, imatinib mesylate, by Druker and colleagues. ⁸³ , ⁸⁴ This was the therapeutic inflection point in CML, changing it from a highly fatal disorder before 2000 to an indolent one, in which patients can anticipate a near‐normal life span, provided they are treated and comply with daily doses of a TKI, are monitored optimally, and change TKI therapy to more effective therapies once resistant disease is identified. Resistance is simply defined as persistence or an increase in BCR::ABL1 transcripts on the International Scale (IS) to >1% after ≥1 year(s) of therapy. The second‐generation, more potent TKIs include dasatinib, bosutinib, and nilotinib. The third‐generation TKIs overcome TKI resistance related to the emergence of the T315I clones, which are resistant to imatinib and the second‐generation TKIs. They are divided into TKIs that target the ABL1 kinase domain (ponatinib, olverembatinib, ELVN‐001) and those that Selectively Target the ABL1 Myristoyl Pocket (STAMP inhibitors; asciminib, TGRX‐678, TERN‐701, and others). ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ , ⁹⁰ , ⁹¹

Responses to TKIs are categorized as a complete cytogenetic response, equivalent to BCR::ABL1 transcripts (IS) <1% (MR2); a major molecular response (MR3 or MMR; BCR::ABL1 transcripts [IS] <0.1%); and deep molecular response (DMR; includes MR4 and MR5; BCR::ABL1 transcripts [IS] <0.01%‐undetectable). Achieving MR2 is associated with near‐normal survival. Achieving a sustained or durable DMR of ≥2 years may offer the opportunity of holding the TKI and attempting a TFR status, in essence, a molecular cure. A durable DMR for 1 to ≥2 years is associated with a TFR rate of 35%–40%, and a durable DMR of ≥5 years results in a TFR rate ≥80%. ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ Achieving a sustained DMR relies on optimal adherence to TKI therapy; consequently, patients may be eligible for TFR in which there is an opportunity to stop treatment completely. ⁹⁶

The aims of CML therapy today are to attain a near‐normal survival; to attempt a TFR; to reduce the incidence of early and late serious, prohibitive, or quality‐of‐life–affecting adverse events (AEs); and to have a TKI that provides a good treatment value (cost vs. benefit) and is affordable to 100% of patients. Five TKIs—imatinib, dasatinib, bosutinib, nilotinib, and asciminib—are approved as CML frontline therapies and are associated with similar near‐normal OS. The newer generation TKIs are associated with faster achievement of MR3 and DMR but have not yet been shown to induce a higher overall rate of durable DMR/TFR. Generic TKIs are now available at low prices compared with patented TKIs. Generic imatinib is available through CostPlus in the United States and in most of the world at <$500 per year. Generic dasatinib at a dose of 50 mg daily is available through CostPlus at a price of approximately $3350 per year. Second‐generation TKI generics are available in many geographies outside the United States at prices between $5000 and $30,000 per year. Therefore, in frontline CML therapy, if OS is the end point, generic imatinib is a good choice. If achieving faster TFR is the end point, then dasatinib is a good treatment option. ⁴ , ⁵ , ⁶ After 25 years of experience with TKIs, and with maturing data, imatinib remains on average the TKI that fulfills best the four aims of CML therapy: it provides near‐normal survival with excellent efficacy (relative 10‐year OS rate, 92%; resistance rate, 1% per year; 10‐year blastic transformation rate, only 5%–6%); the cumulative rate of DMR is 80% at 10 years; it is associated with mostly mild to moderate, nonprohibitive toxicities; and it has a great treatment value (price <$500 per year). ⁹⁷ , ⁹⁸

In the first 10–15 years of CML research, patients who developed AEs on imatinib (or later on other TKIs) were switched to another TKI. This was based on the reality that imatinib was the only approved TKI available at the time and the prevailing notion that reducing the dose could compromise efficacy. Today, we know that reducing the TKI dose to manage AEs in a patient in good molecular response is feasible and that the response can be maintained and improved in most patients. Therefore, in the absence of prohibitive AEs, it is appropriate to manage TKI intolerance through reduction of the TKI dose. ⁸¹ The approved dose of imatinib is 400 mg daily; it can be reduced to 100–300 mg daily. The approved dose of dasatinib is 100 mg daily (50 mg daily is as effective and safer) ⁹⁹ ; it can be reduced to 20–50 mg daily. The approved dose of bosutinib is 400 mg daily for frontline therapy and 500 mg daily for later‐line therapy; it can be reduced to 100–300 mg daily. Also, a dose‐escalation schedule of bosutinib (100 mg daily for 1 week, 200 mg daily for 2 weeks, 300 mg daily for 2–4 weeks, then adjust dose according to response and AEs) will avoid early discontinuation because of self‐limited gastrointestinal toxicities. The approved dose of nilotinib is 300 mg twice daily (on an empty stomach) for frontline therapy and 400 mg twice daily in later‐line therapy; it can be reduced to 150–200 mg daily or 150–200 mg twice daily. The approved dose of ponatinib is 45 mg daily in later line therapy. It can be initiated at 45 mg daily in T315I‐mutated CML and at 30 mg daily in non‐T315I‐mutated CML, with a reduction to 15 mg daily once MR2 is achieved. The approved dose of asciminib is 80 mg daily or 40 mg twice daily in frontline and later‐line therapy, and 200 mg twice daily in T315I‐mutated CML; asciminib 80 mg daily may be reduced to 40 mg daily, but there is little experience with dose‐reduced schedules. ⁴ , ⁵ , ⁶

Prohibitive toxicities are those believed to potentially damage organs, perhaps irreversibly. These include recurrent pleural effusions; pulmonary hypertension; arterio‐occlusive/vaso‐occlusive events; organ itis (pneumonitis, pericarditis, myocarditis, hepatitis, nephritis, enterocolitis); progressive renal failure; neurologic toxicities, which are rare and anecdotal events (progressive neurotoxicity manifesting as dementia‐like or “Lewy body dementia‐like”, parkinsonism, others; increased intracranial pressure). In such instances, a change of TKI is advised, with the choice depending on the type of prior toxicity. Cross‐intolerance to TKIs is more common than thought, manifesting as the same patient experiencing repeated, similar or different AEs on multiple TKIs. When changing TKIs because of AEs in a patient with a good molecular response (MR2 or better), a lower dose of the new TKI may be appropriate. The annual rate of TKI change because of AEs is reported to be 1.5%. This could be reduced with the newer information regarding dose reductions. ⁴ , ⁵ , ⁶ Survival of CML presenting in chronic phase over several decades at MD Anderson is illustrated in Figure 2.

FIGURE 2.

Survival of patients with chronic myeloid leukemia at The University of Texas MD Anderson Cancer Center from 1983 to the present. CML, chronic myeloid leukemia; yr, year.

Resistance to TKI therapy is surprisingly uncommon, about 1% annually. ⁹⁷ The choice of later line therapy for resistance can be a second‐generation TKI in imatinib resistance or a third‐generation TKI in resistance to second‐generation TKIs or in cases of T315I mutation. The choice of later line therapy depends on several factors: patient age, prior TKI exposure and response, prior AEs, patient comorbidities, evolved mutations on prior TKIs, and geographic availability and affordability of TKIs. The management of frontline and later‐line CML therapy, TKI AEs and how to address them, and TKI dose schedules have been detailed in several CML reviews. ⁴ , ⁵ , ⁶

Allogeneic HSCT is a one‐time, cost‐effective, curative therapy. It is associated with serious side effects and a certain degree of mortality (5%–10%), but it offers a potential cure rate of 40%–70%. It should be considered in patients with resistance to second‐generation TKIs, patients with CML in blastic phase, and patients with accelerated phase evolving from chronic phase. In the two latter situations, combinations of TKIs and chemotherapy should be attempted to achieve remission before HSCT. ⁴ , ⁵

The side effects of TKIs are well known, but some require emphasis. For imatinib, they include fluid retention, peripheral and periorbital edema, weight gain, body aches, and, rarely, longer term renal dysfunction. Most are mild to moderate and manageable with dose modifications. The 100‐mg daily dose of dasatinib can cause myelosuppression (10%–20%), pleural effusions (10%–15%), and occasional pulmonary hypertension (1%–2%). These are less frequent with the 50‐mg dose. Nilotinib therapy may be associated with hyperglycemia (10%–15%), exacerbation of diabetes (5%–10%), pancreatitis (1%–3%), and vasospastic/vaso‐occlusive disease (cumulative incidence, 20%–25% at 10 years with 300 mg twice daily, ≥30% with 400 mg twice daily; noted more recently with long‐term follow‐up). Bosutinib can cause diarrhea (10%–30%; usually mild‐to‐moderate, early, and self‐limited), which can rarely progress to serious enterocolitis, liver dysfunction, and renal dysfunction. Serious side effects with ponatinib 45 mg daily include hypertension (20%–30%), vasospastic/vaso‐occlusive disease (10%–15%), skin rashes (5%–10%), and pancreatitis (5%). These are less frequent with ponatinib 15–30 mg daily. Late and progressive renal dysfunction can occur with any of the TKIs and is reversible with treatment interruption and dose reductions. Neurotoxicity mimicking worsening parkinsonism or dementia reverses slowly several months after treatment discontinuation.

Some established traditions over the past 25 years need to be reconsidered, including using optimal TKI dosing to improve tolerability, considering “treatment value” when choosing TKI therapy, and continuing the same TKI in patients with a good molecular response (MR2, MR3). ⁹⁹ Furthermore, recommendations/guidelines from the European LeukemiaNet and the National Comprehensive Cancer Network may be too complicated and may lead to premature changes in a TKI that remains effective. ¹⁰⁰ When it comes to older patients (older than 70 years) not in complete cytogenetic response and in whom the BCR:ABL1 transcripts (IS) remain between >1% and 10%, continuation of an optimal TKI with or without other agents (hydroxyurea, HMAs, low‐dose cytarabine) may control the disease in the chronic phase for more than a decade (10‐year OS rate, 80%), forgoing the need for a potentially curative allogeneic HSCT in favor of disease control with good quality of life. ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ Finally, allogeneic HSCT may be underused today and should be considered for younger patients in chronic phase with resistance to second‐generation TKIs and for patients with T315I‐mutated CML, patients with evolved CML in the accelerated phase, and any patients with CML in the blastic phase. In the latter two situations, achieving a minimal CML burden before allogeneic HSCT (with TKI/chemotherapy combinations) will improve the success rate.

To summarize, with optimal TKI therapy, CML today is associated with near‐normal survival. Although the TFR rate has been stated to be low (15%–30%), with optimized therapy, it should be higher, with an ultimate DMR rate of 80%. If the TKI is discontinued after 5 years of durable DMR, the TFR rate is ≥80%; therefore, the TFR rate is 80% × 80% = 64% (realistically, ≥50% of the total denominator). This figure may be disputed by some CML experts and needs to be confirmed. Future research should address strategies to increase the rate of molecular cure in CML, develop more effective/less toxic TKIs, and make TKIs available and affordable to 100% of patients globally. Some novel third‐generation TKIs under development include olverembatinib and ELVN‐001 (both target the ABL1 kinase domain, like ponatinib), as well as TGRX‐678 and TERN‐701 (STAMP inhibitors, like asciminib).

Chronic lymphocytic leukemia

Currently, CLL is still reported as incurable by most CLL experts and in the literature. ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ However, if cure means that a treatment eliminates clinical disease without recurrence in the patient’s lifetime, then we believe that curative tools and treatments exist today.

Understanding and deciphering the pathophysiology of CLL led to the discovery of the BTK inhibitors, the BCL2 inhibitor venetoclax, and the more potent CD20 antibodies (obinutuzumab), now used in combination regimens that lead to undetectable MRD remission in most patients. The key is to optimize the regimens to eliminate the disease for the patient’s lifetime. Here, the devil is in the details: which combinations; for how long; and how do we measure and follow the elimination of MRD?

Before the discovery of the CLL “treatment trinity” (BTK inhibitors, venetoclax, CD20 antibodies), many patients with CLL were followed by observation alone; and, when a need for therapy arose, the disease was controlled or suppressed with alkylating agents, such as chlorambucil or cyclophosphamide, with or without steroids, vincristine, and other cytotoxic agents. These therapies had little effect on survival. ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸

The discovery of the anti‐CLL efficacy of fludarabine (adenosine nucleoside analog) led to combinations of fludarabine (F) with cyclophosphamide (FC) and rituximab (FCR) in single‐arm trials, then in randomized trials that confirmed the high efficacy of FCR, and its potential to eradicate (and cure) CLL in approximately 40% of patients with favorable‐risk disease (mutated immunoglobulin heavy chain variable [IGHV] CLL; no deletion of 17p or TP53 mutation). ¹¹⁰ , ¹¹¹ , ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ The FCR regimen, originally developed by Michael Keating, became a standard of care in Europe and the United States between 2010 and the 2020s. ¹¹⁰ , ¹¹⁴ FCR was shown to be better than bendamustine‐rituximab combinations (superior rates of progression‐free survival [PFS]). ¹¹⁵ The 10‐year disease‐free survival (DFS) rate with FCR was 55%–60%. ¹¹⁰ , ¹¹⁵

Deciphering of the B‐cell receptor (BCR)‐related CLL pathophysiology and the BTK, PI3 kinase (PI3K) delta, and other pathways related to CLL evolution, and understanding the significance of BCL2 signaling in prolonging CLL cell survival led to the development of several inhibitory small molecules, including ibrutinib, acalabrutinib, and zanubrutinib (covalent BTK inhibitors) and pirtobrutinib and nemtabrutinib (noncovalent BTK inhibitors); idelalisib and duvelisib (PI3K inhibitors); and venetoclax (BCL2 inhibitor). ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ , ¹²⁰ , ¹²¹ , ¹²² , ¹²³ , ¹²⁴ , ¹²⁵ , ¹²⁶ Updates on the efficacy of the combinations of BTK inhibitors plus venetoclax with or without CD20 antibodies (at least 2 years of therapy) might finally establish the high curability of CLL, although long‐term data are awaited. ⁹ , ¹⁰ , ¹¹ Novel BTK degraders (BGB‐16673, NX‐5948, others) and BCL2 inhibitors (sonrotoclax, lisaftoclax) are also demonstrating promising results. ¹²⁷ , ¹²⁸

At MD Anderson, 120 patients with treatment‐naive CLL (aged 65 years and older; or adverse‐risk features, such as deletion 17p, TP53‐mutated, deletion 11q, or unmutated IGHV) received ibrutinib 420 mg daily for 3 months, followed by the addition of venetoclax (weekly ramp‐up to 400 mg daily) for 2 years with the combination. ⁹ , ¹⁰ The bone marrow undetectable MRD rate was 72% (by multiparameter flow cytometry [MFC]), the 5‐year PFS rate was 89.8%, and the OS rate was 95.6% (Figure 3). The 5‐year PFS rate was 86.4% in deletion 17p/TP53‐mutated CLL. The 5‐year PFS rates were also similar in IGHV‐mutated versus unmutated CLL (5‐year PFS rate, 85.7% vs. 90%; p = .79). Thus effective anti‐CLL therapy has reduced the importance of the two long‐established prognostic factors. With a median follow‐up of 5.5 years (all 120 patients were off therapy for at least 3 years), eight patients had CLL recurrence, and five of them required restarting therapy. Two patients developed Richter transformation, and two patients developed MDS. ⁹ , ¹⁰ , ¹²⁹

FIGURE 3.

Survival of patients with chronic lymphocytic leukemia who received treatment with the combination ibrutinib‐venetoclax. OS, overall survival.

Two other studies have reported on a similar combination of ibrutinib‐venetoclax. The CAPTIVATE multicenter trial of fixed‐duration treatment with ibrutinib‐venetoclax (ClinicalTrials.gov identifier NCT02910583) is similar to the MD Anderson study design but delivers ibrutinib‐venetoclax for 1 year only. ¹²⁴ It demonstrated a 5‐year PFS rate of 67%, which was inferior to the MD Anderson results, although the patient characteristics were more favorable (median, age 60 vs. 64.5 years; IGHV‐mutated, 86% vs. 56%). The FLAIR trial (International Standard Randomized Controlled Trial Number ISRCTN01844152) compared ibrutinib‐venetoclax versus continuous ibrutinib therapy versus six cycles of FCR and, on the ibrutinib‐venetoclax arm, delivered for a total duration of at least 2 years, or twice that of the duration to achieve undetectable MRD (duration of therapy, 2–6 years; approximately 50% of patients required >2 years of therapy). It demonstrated an excellent 5‐year PFS rate of 93.9% for the ibrutinib‐venetoclax arm. It also indicated that ibrutinib‐venetoclax was superior to both continuous ibrutinib and FCR, with a 5‐year PFS rate of 93.9% versus 79% versus 58.1%, respectively (ibrutinib‐venetoclax vs. ibrutinib: hazard ratio, 0.29; p < .001). The study excluded deletion 17p (vs. 23% in the MD Anderson study) and had a lower incidence of IGHV‐unmutated patients (48% vs. 86%). ¹²⁶ , ¹³⁰ Thus, we believe that a 2‐year fixed duration therapy with ibrutinib‐venetoclax may be optimal in this setting. ⁹ , ¹⁰ , ¹²⁹

The AMPLIFY trial (ClinicalTrials.gov identifier NCT03836261) compared acalabrutinib‐venetoclax (n = 291) versus acalabrutinib‐venetoclax‐obinutuzumab (n = 286; both arms received 14 courses) versus FCR/bendamustine‐rituximab for six courses (n = 290). The 3‐year OS rates were 93%, 93%, and 75%, respectively (p < .001). There were more deaths related to COVID (coronavirus disease 2019) infections in the acalabrutinib‐venetoclax‐obinutuzumab arm (n = 25) than in the acalabrutinib‐venetoclax arm (n = 10). ¹³¹

In a single‐arm trial at MD Anderson, we investigated the combination of pirtobrutinib‐venetoclax‐obinutuzumab given for 13 courses, with an option to continue therapy for 12 additional courses in MRD‐positive patients. Among the first 80 patients treated, the MRD‐negative rate by next‐generation sequencing (NGS; sensitivity, 10^‐6) was 80% in the bone marrow at 1 year, which was significantly better than our historical experience with ibrutinib‐venetoclax. With a median follow‐up of 1 year, all patients are alive and progression‐free. ¹¹

Several ongoing studies are comparing the efficacy and safety of doublet or triplet regimens containing BTK inhibitors, venetoclax and CD20 antibodies, and different durations of therapy. These will further optimize our CLL management, a disease we consider today to be functionally and molecularly curable.

ALL in younger patients (aged 15–60 years) and Ph‐positive ALL

Pediatric ALL (up to ages 10–12 years) is associated with cure rates ≥80% in single‐center institutional and cooperative trials with intensive chemotherapy regimens (10–15 agents) given over 2.5 to 3 years. ¹³² The cure rates are lower in community practice, particularly among the poor, for whom it may be more difficult to comply with such long‐term, intensive chemotherapy (cure rates, 30%–70%). In adult ALL, these intensive regimens result in 5‐year OS rates of 40%–60% in patients younger than 60 years and of 10%–20% in patients older than 60 years. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹³³ , ¹³⁴ , ¹³⁵

Several therapeutic inflection points, starting in 2008, contributed to altering the treatment and outcomes in ALL: (1) discovering the anti‐ALL efficacy of blinatumomab and inotuzumab and incorporating them into less intensive, shorter regimens in B‐cell ALL; (2) using the more potent BCR::ABL1 TKIs ponatinib and dasatinib in combination with blinatumomab in Ph‐positive ALL (while reducing or eliminating chemotherapy and the need for allogeneic HSCT in first CR); (3) measuring MRD by more sensitive methods, such as the NGS‐MRD assay for IGHV and T‐cell receptors (sensitivity, 10⁻⁶) and changing therapy for low‐burden, detectable disease; and (4) discovering the high efficacy of chimeric antigen receptor (CAR) T‐cell therapy and moving this strategy into minimal‐burden disease and in CR in first and later remissions. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹³⁶ , ¹³⁷ , ¹³⁸ , ¹³⁹ , ¹⁴⁰ , ¹⁴¹ , ¹⁴² , ¹⁴³ , ¹⁴⁴ , ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰

Numerous discussions and debates are centered on whether pediatric intensive regimens (which rely on higher doses schedules of nonmyelosuppressive agents, such as vincristine, steroids, and particularly asparaginase) or hyper‐CVAD‐ (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone)–based regimens (myelosuppressive) are better. ¹⁵¹ , ¹⁵² , ¹⁵³ , ¹⁵⁴ , ¹⁵⁵ In the modern era of ALL therapy, it is an outdated debate. Today, the important research questions should revolve around optimizing the shorter, less intensive chemotherapy combinations with CD19/CD22–targeted therapy and then, if needed, to compare them with the old intensive regimens.

Frontline therapy of younger ALL at MD Anderson and brief review of experiences from other research groups

At MD Anderson, we developed the hyper‐CVAD regimen in 1992, ¹⁵⁶ , ¹⁵⁷ added rituximab in 2000 to the treatment of Burkitt lymphoma and pre‐B ALL (high expression of CD20), ¹⁵⁸ , ¹⁵⁹ and reported better outcomes compared with the historical results from hyper‐CVAD alone, although single‐agent rituximab is not active in ALL. Randomized trials of chemotherapy with or without rituximab confirmed the results. ¹⁶⁰ , ¹⁶¹ Because of emerging data suggesting that pediatric‐inspired regimens were superior to the old adult ALL regimens (which did not adopt the principles of pediatric treatments), in 2006–2012, we used the pediatric‐inspired, augmented Berlin–Frankfurt–Münster regimen in patients younger than 40 years and produced results similar to those produced with hyper‐CVAD. ¹⁵³ , ¹⁵⁴ In 2012, we reverted to hyper‐CVAD plus ofatumumab for patients with B‐cell, Ph‐negative ALL and reported 4‐year EFS and OS rates of 60% and 68%, respectively. The 4‐year survival rate was 74% in patients younger than 40 years. ¹⁶² We have continued to use the hyper‐CVAD regimen, optimized with the inclusion of pegylated asparaginase, nelarabine, and venetoclax, for the treatment of T‐cell ALL, which has resulted in a 2‐year survival rate of 88%. ¹⁶³

After discovery of the efficacy of blinatumomab by Topp and German investigators and of inotuzumab in MD Anderson investigator‐initiated studies, ¹³⁸ , ¹³⁹ , ¹⁴⁰ randomized trials confirmed their superiority as single agents over standard‐of‐care intensive chemotherapy in refractory‐relapsed ALL, resulting in their regulatory approvals. ¹⁴¹ , ¹⁴² However the benefits of these costly therapies were modest when used as single agents in the approved indications. In 2010, this led to exploring the addition of inotuzumab and (later) blinatumomab to a reduced chemotherapy regimen, mini‐hyper‐CVD (dose‐reduced hyperfractionated cyclophosphamide, vincristine, and dexamethasone), in both later line ALL therapy and as frontline therapy in older patients with ALL. In 2015, we designed a frontline hyper‐CVAD plus sequential blinatumomab regimen for younger patients with pre‐B ALL (younger than 60 years) and later added fractionated, lower dose inotuzumab. Among the first 75 patients treated, the CR rate was 100%, the MFC MRD‐negative rate was 95%, and the NGS‐MRD–negative was rate 76%. The 3‐year OS rate was 90%, and the 3‐year EFS rate was 85%. The OS and RFS rates were better when both inotuzumab and blinatumomab were incorporated. ¹⁶ , ¹⁶⁴

Future modifications could include adding CD20 bispecific T‐cell engagers in view of their efficacy in lymphoma by using subcutaneous blinatumomab; using blinatumomab simultaneously with chemotherapy (rather than sequentially), as reported in the “dose‐dense mini–hyper‐CVD” experience; using CAR T‐cells in lieu of allogeneic HSCT; and monitoring NGS‐MRD in all patients and modifying therapy based on the results. ¹⁴⁵ , ¹⁶⁵ , ¹⁶⁶ , ¹⁶⁷

Monitoring MRD using NGS techniques allows the detection of residual ALL disease at very low levels (sensitivity, 10^‐6) and should help both in B‐cell ALL (monitoring IGHV‐rearranged clones) and in T‐cell ALL (monitoring T‐cell receptor [TCR] clones). MRD‐negative ALL disease measured by MFC does not protect from relapse (still 30%–40%); NGS‐MRD–negative ALL disease at CR (or within the first 3 months of CR) is associated with a relapse rate ≤5%. Detecting even small amounts of ALL (such as 5–10 leukemic cells/10⁶) allows very early treatment modifications (adding inotuzumab or blinatumomab, CAR T‐cells, allogeneic HSCT) and may improve the success rate. ¹⁵⁰ , ¹⁶⁸

Survival results in younger patients with ALL at MD Anderson over 5 decades are illustrated in Figure 4.

FIGURE 4.

Survival of younger patients with acute lymphoblastic leukemia from 1983 to the present (MD Anderson data). +/− indicates with or without; HCVAD, hyper‐CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone); mos, months; OS, overall survival; VAD, vincristine, adriamycin (doxorubicin), and dexamethasone; yr, year.

Other research groups have explored similar research trends, mostly investigating blinatumomab sequentially after chemotherapy. For example, the Italian GIMEMA LAL 2317 study, the French GRAALL‐2014 study, and the Dutch/Belgian HOVON‐146 study were single‐arm trials using blinatumomab with pediatric‐inspired regimens, reporting CR rates of 85%–100%, MRD‐negative rates ≥90%, and 3‐year or 4‐year OS rates of 75%–86% in younger patients. ¹⁶⁹ , ¹⁷⁰ , ¹⁷¹

Litzow and colleagues reported on the ECOG‐ACRIN E1910 trial, in which 488 patients were treated with three courses of intensive chemotherapy. The 224 patients (48% of the total) who achieved MRD negativity were then randomized to receive either four additional courses of blinatumomab or continue standard chemotherapy. The investigators reported a significant benefit from adding blinatumomab: a 3‐year OS rate of 85% versus 68% (hazard ratio, 0.41; p = .002) from the time of randomization. ¹⁷²

Ph‐like ALL constitutes about 15%–25% of adult ALL (more frequent among Hispanics) and is divided into two categories. The first and smaller category (10%–15% of Ph‐like ALL) consists of patients who have ABL1‐class fusions (ABL1/ABL2, CSF1R, and PDGFRB). These should be treated like Ph‐positive ALL with the addition of BCR::ABL1 TKIs to chemotherapy and/or blinatumomab. ¹⁷³ , ¹⁷⁴ , ¹⁷⁵ The second and larger category (85%–90% of Ph‐like ALL) comprises patients with CRLF2 rearrangement/overexpression with or without JAK1/2 mutations (the latter being worse). These patients benefit from the novel regimens incorporating blinatumomab/inotuzumab and chemotherapy and may require allogeneic HSCT in first CR if they have persistent NGS‐MRD positivity or high‐risk features (JAK mutations). ¹⁶ , ¹⁶⁴

Frontline therapy of Ph‐positive ALL at MD Anderson and brief review of experiences from other research groups

Before 2000, pediatric Ph‐positive ALL treated with intensive chemotherapy was associated with a 5‐year OS rate of 30%–35%. The 5‐year OS rate in adult Ph‐positive ALL was <10% and increased to 35%–40% if patients underwent allogeneic HSCT in first CR. At that time, Ph‐positive and KMT2A‐rearranged disease were the two worst ALL subsets. ¹² , ¹³ , ¹⁴ , ¹⁷⁶ , ¹⁷⁷

Then, two major therapeutic inflection points occurred. The first was the addition of imatinib to hyper‐CVAD or other intensive chemotherapy regimens, starting in 2000. The second was replacing intensive chemotherapy with blinatumomab in 2017 and later, deciding on the need for allogeneic HSCT in first CR based of the persistence of BCR::ABL1 transcripts or NGS‐MRD disease.

Adding imatinib to hyper‐CVAD chemotherapy resulted in 5‐year OS rates of 40%. ¹⁷⁸ Replacing imatinib with potent second‐generation TKIs (dasatinib, nilotinib) improved the 5‐year OS rates to 45%–50%. ¹⁷⁹ , ¹⁸⁰ A randomized trial of intensive chemotherapy plus dasatinib versus imatinib in pediatric disease demonstrated a benefit for dasatinib, with a 4‐year OS rate of 88% versus 69% (p = .04) and reduced incidence of both systemic (20% vs. 34%; p = .01) and CNS relapses (2.7% vs. 8.4%; p = .06). ¹⁸¹ Ponatinib plus intensive chemotherapy further improved the results (5‐year OS rate, 75%), ¹⁸² , ¹⁸³ and the superiority of ponatinib was supported by a meta‐analysis and propensity‐matched score analyses. ¹⁸⁴ , ¹⁸⁵ , ¹⁸⁶ A multicenter, randomized phase 3 trial (PhALLCON; ClinicalTrials.gov identifier NCT03589326) of low‐intensity chemotherapy plus ponatinib versus imatinib demonstrated a 3‐month MRD‐negative CR rate (postinduction; primary study end point) that was higher with ponatinib (34.4% vs. 16.7%; p = .002), resulting in regulatory approval of ponatinib as frontline therapy for Ph‐positive ALL by the US Food and Drug Administration. The incidence of arterio‐occlusive events was surprisingly low with ponatinib and was comparable to that with imatinib (2.5% vs. 1.2%). ¹⁸⁷

Between 2010 and 2017, five changes were implemented in the hyper‐CVAD–TKI regimens. The first change was replacing dasatinib with ponatinib in 2010, based on the observation that 75% of relapses were caused by the emergence of a T315I‐mutated clone. ¹⁸⁸ The second change was increasing the number of intrathecal prophylactic chemotherapy courses from eight to 12 because it was noted that, as patients were living longer, CNS relapses were occurring in 15% of cases. ¹⁸⁹ The number of intrathecal courses was further increased to 15 around 2020, once CNS relapses were noted again after the removal of intensive systemic chemotherapy, particularly the high‐dose methotrexate‐cytarabine courses, which provided additional protection from CNS relapse. The third change was replacing intensive systemic chemotherapy with blinatumomab after documenting the superior efficacy of the latter. ¹⁹⁰ , ¹⁹¹ Blinatumomab is given simultaneously during induction with ponatinib (once the peripheral blast count is reduced to <2 × 10⁹/L using dexamethasone 20–40 mg daily for 4 days, with or without using also a single dose of vincristine 1–2 mg). Blinatumomab is given for a total of five courses. The fourth change was using allogeneic HSCT in first CR only in patients with persistent molecular MRD (positive BCR::ABL1 transcripts or NGS‐MRD disease; later only if NGS‐MRD–positive). The fifth change was reducing ponatinib during induction from 45 to 30 mg daily, and further reducing it to 15 mg daily once molecular CR was documented (ponatinib 45 mg daily is toxic; we also add daily baby aspirin in CR). A sixth modification was implemented in 2024: Because we observed a higher incidence of systemic and CNS relapse in patients presenting with WBC counts from >70 to 75 × 10⁹/L, in this subset, we reintroduced two courses of high‐dose methotrexate‐cytarabine as courses 3 and 4 of blinatumomab chemotherapy (blinatumomab starting on day 5 of chemotherapy for 18 days; total blinatumomab courses still five; total ponatinib duration ≥5 years). It is possible that, in the future, ponatinib may be held after ≥5 years of negative NGS‐MRD status. ¹⁹²

Among the first 84 patients treated with the simultaneous ponatinib‐blinatumomab regimen, the CR rate was 97%, the NGS‐MRD–negative rate was 95%, and the 4‐year OS rate was 88%. Only two patients were referred to allogeneic HSCT in first CR. Ten relapses were observed (five CNS relapses and five systemic relapses with or without CNS involvement), almost all in patients who had high WBC counts at presentation. Of note, 10%–25% of patients achieve NGS‐MRD–negative disease but have persistence of BCR::ABL1–positive transcripts. These patients have a Ph‐positive signal emanating from nonlymphoblastic clones, likely from myeloid Ph‐positive cells. They do not relapse with ALL, nor do they require allogeneic HSCT in first CR. However, discontinuation of ponatinib after 5 years of NGS‐MRD–negative disease may not be a consideration in such patients. ¹⁷

To summarize, with a mostly nonchemotherapy, ponatinib‐blinatumomab–based regimen, Ph‐positive adult ALL has transformed from being the most unfavorable subset to the most favorable ¹⁷ , ¹⁹⁰ (Figure 5).

FIGURE 5.

Survival in Philadelphia chromosome‐positive acute lymphoblastic leukemia from 1984 to the present (MD Anderson data). HCVAD, hyper‐CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone); mos, months; OS, overall survival; yr, year.

Different research groups have approached Ph‐positive ALL from various angles over time. Ribera and Spanish colleagues reported on intensive chemotherapy plus ponatinib induction in 30 patients (median age, 50 years; age range, 20–59 years); all were offered allogeneic HSCT early in first CR. The CR rate was 100%, the complete molecular remission (CMR) rate was 68% before HSCT, and 28 of 30 patients (93%) underwent HSCT in first CR. The 2‐year EFS rate was 91%. ¹⁸³ , ¹⁸⁶

Pfeifer and German colleagues reported their experience in treating 174 younger patients (median age, 42 years; age range, 18–55 years) with imatinib 600 mg daily and low‐intensity chemotherapy, followed in CR by allogeneic HSCT. The CR rate was 95%, and HSCT was completed in 159 of 174 patients (91%; 98% of CRs). The CMR rate was only 42% after three courses of chemotherapy (pre‐HSCT). The 3‐year OS rate was 76%, and the treatment‐related mortality was 16% (mostly from HSCT, which is high even in this relatively young population). ¹⁹³

Several European studies have investigated the use of TKIs with minimal chemotherapy in older patients with Ph‐positive ALL. The 5‐year OS rate ranged from 30% to 45%, still with high reliance on HSCT in first CR (30%–72%).

Foà and Italian colleagues treated 63 patients (median age, 54 years; age range, 24–82 years) with dasatinib 140 mg daily (plus steroids during the first month of induction) and the later addition of sequential blinatumomab (3 months from start; from two to five courses). The response rate was 100%, the molecular response rate was 60%, and the CMR rate was 41%. Forty‐eight percent of those patients underwent allogeneic HSCT in CR, and nine relapses were reported. The 4‐year OS rate was 82%. ¹⁵ Chiaretti and Italian colleagues reported on 133 patients (median age, 57 years; age range, 20–87 years) who received a similar sequential ponatinib‐blinatumomab regimen. The CR rate was 95%, and the MRD‐negative rate was 73% after two blinatumomab consolidations. Only 12% of patients underwent allogeneic HSCT in first CR. The estimated 18‐month OS rate was 95%. ¹⁹⁴

To summarize, currently, Ph‐positive adult ALL is a potentially highly curable entity with chemotherapy‐free regimens using blinatumomab and potent TKIs (ponatinib, dasatinib), with limited reliance on allogeneic HSCT. ¹⁹⁵ A subset of patients with higher risk for systemic/CNS relapse (identified simply by presenting leukocytosis >70 × 10⁹/L; also possibly by molecular testing [deletion of IKZF1 at 7p12.2 plus other mutations; deletion of VPREB1 at 22q11.22]) may require reintroducing some systemic, high‐dose methotrexate‐cytarabine consolidation chemotherapy and more intrathecal prophylaxis administrations. Finally, TKI therapy may not necessarily need to be used for a lifetime. As in CML, treatment discontinuation after 5 years in CMR may be possible, but this needs to be investigated. ¹⁹²

THE INTERMEDIATE LEUKEMIAS

ALL in patients older than 60 years

Historically, older patients who had ALL treated with standard intensive or attenuated chemotherapy resulted in CR rates of 70%–80% and 5‐year OS rates of 10%–15%. ¹⁹⁶ Adding inotuzumab and blinatumomab to lower intensity chemotherapy resulted in improved results compared with historical data from chemotherapy alone. ¹⁹⁷ , ¹⁹⁸ , ¹⁹⁹

At MD Anderson, we investigated low‐intensity chemotherapy with mini‐hyper‐CVD, initially in combination with inotuzumab and later with the addition of sequential blinatumomab (four courses). Maintenance was done with 1 year of POMP (6‐mercaptopurine, vincristine, oral methotrexate, and prednisone) plus blinatumomab every 3 months. Among 80 treated patients (median age, 68 years; age range, 60–87 years), the CR rate was 89%, the overall response rate was 99%, and the MFC‐MRD–negative rate was 94%. The median OS was 61.6 months, and the 5‐year OS rate was 50%, which is almost twice that of our historical data with dose‐adjusted hyper‐CVAD. The 3‐year PFS rate was 49% with mini‐hyper‐CVD plus inotuzumab and 65% with the addition of blinatumomab (p = .76). The 5‐year cumulative incidence of relapse was only 20%, but the mortality rate in CR was 26 of 80 patients (33%), with 14 of 26 deaths related to ALL or therapy (sepsis, n = 9; sinusoidal obstruction syndrome, n = 3; post‐allogeneic HSCT, n = 2), mostly among patients older than 70 years. Therapy‐related myeloid neoplasms developed in eight of 80 patients (10%), also mostly in patients older than 70 years and in those harboring TP53 mutations. ¹⁹⁸ Based on these results, we are currently exploring inotuzumab plus blinatumomab with less chemotherapy, followed by CAR T‐cell therapy.

Several groups have also investigated lower intensity chemotherapy in combination with inotuzumab or sequential blinatumomab.

Stelljes and German colleagues reported on 45 patients who received a low‐intensity chemotherapy “prephase” (cyclophosphamide, vincristine, and steroids), followed by fractionated inotuzumab induction‐consolidation, followed by five courses of consolidation chemotherapy and 1 year of maintenance with 6‐mercaptopurine plus methotrexate. Among 43 evaluable patients (median age, 64 years; age range, 56–80 years), the CR/CRi (CR with incomplete recovery of platelets and/or absolute neutrophil count) rate was 100%, the MRD negativity rate was 74%, the 2‐year OS rate was 81%, and the 2‐year EFS rate was 73%. ¹⁹⁹

Chevallier and French colleagues used a similar strategy (prephase; inotuzumab; chemotherapy; then POMP maintenance for 1.5 years) in 131 patients (median age, 68 years; age range, 55–84 years) and reported a CR/CR with incomplete recovery of platelets rate of 90%. The 2‐year OS rate was 55%, and the EFS rate was 46%. ²⁰⁰

AML in patients younger than 60 years

The combination of cytarabine and anthracyclines (the “7 + 3 regimen”) is still acknowledged as the standard of care in AML by many AML experts and in community practice. We believe there are better intensive chemotherapy regimens for younger/fit patients that incorporate adenosine nucleoside analogs and high‐dose cytarabine in induction and consolidation: FLAG‐IDA, or cladribine plus high‐dose cytarabine‐IDA (CLIA). Although regimens with HMAs plus venetoclax (azacitidine plus venetoclax, decitabine plus venetoclax) are now approved as a new standard of care in older/unfit AML, better results may be obtained with the “triple nucleosides plus venetoclax” regimen (cladribine and low‐dose cytarabine plus venetoclax alternating with HMA plus venetoclax). ⁴³ , ⁴⁴ , ⁶³ , ⁶⁴ , ²⁰¹ The approval of several targeted therapies for different AML indications and the availability of others for non‐AML indications open new venues for incorporating them into frontline and later line therapy. These include venetoclax, FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, sorafenib), IDH1/IDH2 inhibitors (ivosidenib, olutasidenib, enasidenib), GO, the oral HMAs (oral azacitidine with limited oral bioavailability; fully bioavailable oral decitabine plus cedazuridine), and menin inhibitors (revumenib, ziftomenib, bleximinib, enzomenib). These are now being incorporated into both intensive regimens, such as FLAG‐IDA plus venetoclax, FLAG‐IDA‐GO, CLIA plus venetoclax, FLAG‐IDA/CLIA or 7 + 3 plus FLT3 or IDH inhibitors, 7 + 3 plus venetoclax, and intensive chemotherapy plus menin inhibitors. They also are being investigated in triplet/quadruplet combinations, such as azacitidine/decitabine‐venetoclax plus FLT3, or IDH inhibitors, or GO, or menin inhibitors. ²² , ²³ , ²⁰² As more targeted therapies are combined, cumulative myelosuppression and its complications become serious considerations, requiring refinement of these regimens to improve efficacy/OS without increasing mortality. ⁷⁰ , ²⁰³ , ²⁰⁴ , ²⁰⁵ , ²⁰⁶ , ²⁰⁷

The 7 + 3 regimen is associated with 5‐year OS rates of 35%–40% in younger/fit AML, a median OS <1 year, and a 5‐year OS rate of <20% in older/fit AML. ²⁰⁸ , ²⁰⁹ The HMA plus venetoclax regimen is associated with a 3‐year OS rate of 20%–25% in older/unfit AML. ²¹⁰ These results strongly depend on the inclusion criteria of different trials and patient and leukemia characteristics, such as median age and upper age limit, performance status, patient comorbidities and organ dysfunctions, and the inclusion of TP53‐mutated AML and TS‐AML. Outcomes also depend on leukemia expertise and the availability of supportive care/use of prophylactic antibiotics/antifungals. These are reviewed elsewhere. ⁶³ , ⁶⁴

Before the development and approval of targeted therapies in AML beginning in 2017, several earlier strategies contributed to improving the outcome of the 7 + 3 regimen. These included (1) the use of high‐dose cytarabine consolidation (3–4 courses); (2) optimization of the daunorubicin dose schedule to 60 mg/m² daily for 3 days as induction (45 mg/m² for 3 days [less effective]; 90 mg/m² daily for 3 days [not more effective and more toxic]); developing IDA and other anthracyclines (IDA 12 mg/m² daily for 3 days with cytarabine, 8–10 mg/m² daily for 3 days with other additions [FLAG‐IDA plus venetoclax, CLIA plus venetoclax]); (3) confirming the value of GO in AML and later refining its dose schedule in frontline AML therapy; (4) refinement of the allogeneic HSCT procedures, improvement of its efficacy/safety results, and strengthening its role in first and later remissions; and (5) improvements in antibiotic/antifungal and other supportive care measures, which reduced myelosuppression‐related mortality. ⁶³ , ⁶⁴

The FLAG‐IDA plus venetoclax and CLIA plus venetoclax regimens continue to produce very encouraging results in studies from MD Anderson ²⁰ , ²¹ , ²⁰⁵ , ²¹¹ and elsewhere, as do earlier studies of FLAG‐IDA‐GO in AML and its subsets (NPM1‐mutated and FLT3‐mutated AML) in studies in the United Kingdom, Italy, and other countries.

At MD Anderson, younger, fit patients (aged up to 60–65 years) with AML are treated with FLAG‐IDA plus venetoclax or CLIA plus venetoclax. ²⁰ , ²¹ , ²⁰⁵ Comparing these regimens with similar historical ones without venetoclax demonstrated its benefit in terms of improving OS and DFS, particularly in patients with intermediate‐risk and adverse‐risk disease. ²⁰³ Among 95 patients (median age, 48 years) treated with CLIA plus venetoclax, the CR/CRi rate was 95%, the MFC‐MRD negativity rate was 90%, and the 3‐year OS rate was 73%. ²⁰⁵ Among 68 patients treated with FLAG‐IDA plus venetoclax, the CR/CRi rate was 96%, the MFC‐MRD negativity rate was 89%, and the 2‐year OS rate was 75%. ²¹ , ²¹¹ Outcomes on average were better with allogeneic HSCT in first CR versus consolidation therapy. Similar data were reported with combinations of other intensive regimens (7 + 3, 5 + 2) and venetoclax. ²⁰⁷ , ²¹²

It has been demonstrated that adding FLT3 inhibitors to intensive chemotherapy benefits patients with FLT3‐mutated AML, in single‐arm and randomized trials. In the RATIFY trial (ClinicalTrials.gov identifier NCT00651261) randomizing 717 patients (younger than 60 years; median age, 48 years) with FLT3‐mutated AML to 7 + 3 with or without midostaurin, the addition of midostaurin improved OS (median OS, 74.7 vs. 25.6 months; 5‐year OS rate, 50% vs. 42%; p = .009). ²¹³ In the QuANTUM‐First trial (ClinicalTrials.gov identifier NCT02668653) randomizing 539 patients with FLT3‐internal tandem duplication AML to 7 + 3 with or without quizartinib, the addition of quizartinib improved OS (median OS, 31.9 vs. 15.1 months; 3‐year OS rate, 50% vs. 42%; p = .032). ²⁹ In our single‐arm trials of CLIA plus FLT3 inhibitors in FLT3‐mutated AML, we have observed 3‐year OS rates ≥70%. ²⁰⁷ Thus the new strategies using intensive chemotherapy plus FLT3 inhibitors, allogeneic HSCT in first CR, and post‐HSCT maintenance with FLT3 inhibitors have changed FLT3‐mutated AML from an intermediate/adverse subset to a potentially favorable subset. Real‐world data reported similar benefits. Of note, non–FLT3‐targeting strategies (the use of high‐dose cytarabine, high‐dose daunorubicin or IDA; the addition of GO, cladribine, or venetoclax) have also been shown to improve outcomes in FLT3‐mutated AML. ⁶³ , ⁶⁴ The use of FLT3 inhibitors post‐HSCT in FLT3‐mutated AML has also shown benefit, particularly among patients with MRD‐positive disease before and after HSCT. ²¹⁴ A Spanish trial in FLT3 wild‐type AML showed that the addition of quizartinib to 7 + 3 chemotherapy improved OS (2‐year OS rate, 63% vs. 47%; p = .004). ²¹⁵ The benefit may be demonstrable only in patients who have an FLT3‐like molecular signature, essentially enriched in NPM1, DNMT3A, FLT3‐tyrosine kinase domain, and IDH2 mutations. ²¹⁶ , ²¹⁷

The addition of IDH inhibitors to intensive chemotherapy in IDH1/IDH2‐mutated AML has also demonstrated efficacy. Among 151 patients with newly diagnosed IDH1/IDH2‐mutated AML who received 7 + 3 and ivosidenib (60 patients with IDH1 mutation) or enasidenib (91 patients with IDH2 mutation), the overall response rate was 78%. ²⁸ A large, randomized phase 3 study of intensive chemotherapy with ivosidenib or enasidenib in IDH1‐mutated or IDH2‐mutated patients, respectively, has completed enrollment, with results forthcoming. Studies are ongoing to evaluate the addition of menin inhibitors to intensive chemotherapy in KMT2A‐mutated and NPM1‐mutated AML.

Future improvements in younger AML include optimizing the benefit/risk of strategies that combine chemotherapy with more than one targeted therapies (e.g., GO plus venetoclax, GO plus FLT3 or IDH inhibitors, venetoclax plus FLT3/IDH inhibitors) in simultaneous or sequential approaches. There is some debate about initial studies investigating lower intensity regimens in younger patients, especially those who are destined to undergo allogeneic stem cell transplantation in first remission. However, the data are premature, and this approach cannot be recommended outside clinical trials. The use of the MRD assessment, especially with the more sensitive molecular assays, may provide additional data on the effectiveness of such strategies, and perhaps the MRD assessment may be used as a surrogate end point for outcomes in the future.

Allogeneic HSCT continues to play an important role in AML in first CR. The procedure is safer, more effective, and encompasses a broader group of eligible patients (older patients, matched unrelated donors and haplo‐matched donors; cyclophosphamide Day 4 post‐HSCT) in 2025 than in the 1980s. ⁶³ , ⁶⁴

THE UNFAVORABLE LEUKEMIAS

Older AML and higher risk MDS

In general, older patients with AML are considered those over 60, but opinions differ regarding whether the age cutoff should be 65, 70, 75 years, or even older. Declaring a patient unfit for intensive chemotherapy can be subjective and is closely related to older age. Hence, there are endless ongoing discussions about which patients should be considered unfit. At MD Anderson, we generally use age 60 years and older as a cutoff to offer lower intensity chemotherapy (CBF AML excluded), regardless of fitness. This is based on the poor results of 7 + 3 intensive chemotherapy in patients older than 60 years, in whom the median OS was <1 year, and the 3‐year OS rate was <15%. The lower intensity strategy has paid off given that our recent trials of triple nucleosides plus venetoclax (cladribine, low‐dose cytarabine, plus venetoclax alternating with HMA) and of triplet regimens with HMAs (HMAs with venetoclax plus a third targeted agent) appear to be as effective and safer than intensive chemotherapy.

Older patients who are fit for intensive chemotherapy and have favorable or intermediate‐risk features can still be offered dose‐adjusted schedules of the more intense regimens outlined above. For instance, Chua and colleagues reported that an attenuated regimen of 5 + 2 plus venetoclax (cytarabine for 5 days, IDA for 2 days, venetoclax for 14 days) in 51 older patients (aged 65 years and older or 60 years and older with monosomal karyotype; median age, 72 years; age range, 62–80 years) with both de novo and secondary AML resulted in a CR rate of 41% and a CR+CRi rate of 72%. However, the median OS was only 11.2 months. In de novo AML, the CR rate was 68%, the CR+CRi rate was 97%, and the median OS 31.3 was months. ²⁰⁷

However, most patients with AML are older than 60 years, and the median age is 68–70 years. Thus, although these difficult leukemias occupy a minor footprint in this review, with an AML incidence of 20,800 cases in the United States in 2024, about 60% (12,500 patients) have no reasonable standard‐of‐care options. To this number are added younger patients who may be unfit for intensive chemotherapy (because of poor performance status or comorbidities) and those who have historically done poorly on intensive chemotherapy regimens (e.g., TS‐AML post‐MDS or post‐MPN AML, TP53‐mutated AML, MECOM‐rearranged AML, complex‐karyotype AML). ⁶³ , ⁶⁴ Hence the urgent need to make rapid progress in these subsets.

Before 2000, many older patients with AML were offered palliative/supportive care or hospice. At that time, the median OS was <3 months or 4–6 months with intensive chemotherapy, and two thirds of patients were not offered therapy. The proportion of patients offered no chemotherapy decreased to 43% in 2013. ²¹⁸

The outlook started changing around 2000 with the discovery of the activity of HMAs through the work of Lewis R. Silverman with azacitidine and the MD Anderson investigator‐initiated studies of decitabine as epigenetic therapy (starting in 1992). These efforts culminated in regulatory approvals of HMAs for the treatment of MDS and AML in different geographies. However, the OS benefits were modest, although HMAs gained gradual penetration in the treatment of older/unfit AML. ²¹⁹ , ²²⁰ , ²²¹ , ²²² , ²²³ , ²²⁴ , ²²⁵ Along the research path, low‐dose cytarabine and cladribine plus low‐dose cytarabine were identified as safe and active in older patients with AML. ²²⁵ , ²²⁶ , ²²⁷

The discovery of the anti‐AML activity of venetoclax led to single‐arm and later randomized trials that established the combination of HMAs plus venetoclax as a new standard of care for the treatment of older/unfit AML. ¹⁸ , ²²⁸ , ²²⁹ , ²³⁰ However, this regimen offered modest benefits (median OS, 14.7 months; 3‐year OS rate, 25%; CR/CRi rate, 66.4%). ²¹⁰ To improve on these results, we opted for two strategies. The first was to add targeted therapies to the HMA plus venetoclax backbone when feasible. The second was to investigate the triple nucleosides plus venetoclax regimen. We also moved gradually to the use of the fully absorbable oral decitabine as an alternative to the parenteral formulation. ²³¹ This offers the benefit of all‐oral couplet or triplet regimens with oral decitabine, venetoclax, and, if indicated, a third oral targeted agent (FLT3, IDH, or menin inhibitors). ²³² These investigational strategies are paying off.

In IDH1/IDH2‐mutated AML, the combination of HMA plus venetoclax or HMA plus an IDH inhibitor resulted in a median OS of 10.2–24 months. ²³³ , ²³⁴ A triplet regimen of azacitidine, venetoclax, plus an IDH inhibitor in 60 newly diagnosed patients with IDH1/IDH2‐mutated AML resulted in a composite CR (CRc) rate of 92% and a 2‐year OS rate of 69%. Among 43 patients with de novo AML, the CRc rate was 98%, and the 2‐year OS rate was 84%. ²⁰²

In FLT3‐mutated AML, the combination of azacitidine plus venetoclax resulted in a median OS of 11.5–13.3 months. ²³⁵ The triplet of HMA, venetoclax, plus an FLT3 inhibitor resulted in a CR rate of 90% and a 2‐year OS rate of 72%. ²³

In refractory/relapsed, KMT2A‐rearranged AML or NPM1‐mutated AML, single‐agent menin inhibitors resulted in response rates of 20%–50% and short OS. The triplet of revumenib, oral decitabine, and venetoclax (venetoclax for 14 days, then reduced to 5–10 days; the SAVE regimen) resulted in an overall response rate of 82% and a 12‐month OS rate of 51% in the refractory/relapsed setting. ²⁰⁶ A similar regimen of revumenib, azacitidine, and venetoclax (venetoclax daily) in older patients (median age, 70 years; age range, 60–92 years) who had newly diagnosed AML resulted in a CRc rate of 81% and a median OS of 15.5 months in 34 patients with NPM1‐mutated AML, and a CRc rate of 89% and median OS of 18 months in nine patients who had KMT2A‐rearranged disease. Of 43 deaths, there were five early deaths and six deaths in CR. ²³⁶ In such regimens, the results may be strongly influenced by the treatment design, the schedule of drugs, and the supportive care measures. This high mortality may be caused by the daily dose schedule of venetoclax used and perhaps the inconsistent use of antibiotic prophylaxis. Thus the results can be improved with shorter durations of venetoclax to avert prolonged myelosuppression. We favor only 14 days during induction, performing a day‐14 bone marrow assessment and deciding on continuing the third targeted agent (particularly the FLT3 inhibitor) based on the day‐14 persistence of AML. For comparison, the CRc rates in these two subsets of triple nucleosides plus venetoclax are ≥90%, and the 3‐year OS rates are >60%.

To improve the results in older, unfit patients with AML, MD Anderson researchers pioneered the use of the triple nucleosides plus venetoclax regimen, consisting of cladribine, low‐dose cytarabine, venetoclax induction, and consolidation followed by alternating cycles of this with azacitidine or oral decitabine combined with venetoclax. Among 190 patients treated (median age, 68 years; age range, 54–84 years), the CR rate was 78%, the CR + CRc rate was 84%, and the 4‐year OS rate was 52%. ²² , ²³⁷ Eighty patients underwent allogeneic HSCT in CR. By landmark analysis, OS was better with HSCT (2‐year OS rate, 84.2% vs. 54.2%; p < .001). These results compare favorably with our historical experience and need to be investigated in larger cooperative trials.

A subset of patients with higher risk MDS may benefit from the AML treatments outlined above. The most clear‐cut group perhaps comprises patients younger than 60–65 years who have bone marrow blasts >8%–10% and a normal or nonadverse karyotype. ²³⁸ In such patients, intensive regimens combined with targeted therapies (like FLAG‐IDA plus venetoclax or CLIA plus venetoclax) followed by allogeneic HSCT in first CR, when feasible, may be curative. In a recent update of the study evaluating CLIA plus venetoclax in patients with newly diagnosed MDS who had increased blasts, the overall response rate was 100%, with 2‐year and 4‐year OS rates of 100% after a median follow‐up of 2.9 years. In older patients (older than 65 years) who have higher blast counts and normal karyotype, the triple nucleosides plus venetoclax regimen followed by allogeneic HSCT also may be beneficial.

SUMMARY

Freireich and colleagues, the inaugural giants in leukemia and cancer research, summarized one half a century of discoveries in leukemia in their American Society of Clinical Oncology 50th anniversary editorial in 2014. ¹ Cancer knowledge is quite contemporary and is changing very rapidly; thus, it is a happy surprise that so much progress occurred across all leukemias since then. For example, that 2014 editorial only briefly mentioned the discoveries of blinatumomab and inotuzumab in ALL, but combinations of these antibodies with chemotherapy in B‐cell ALL or with ponatinib in Ph‐positive ALL or CAR T‐cell research were still in their infancy. The CLL section mentioned the development of ibrutinib in a single sentence, and nothing was then available on the curative potential of the BTK inhibitors plus venetoclax combinations. None of the AML discoveries were mature at that time (approvals of all 13 drugs in AML happened since 2017). Thus today, in 2025, we find ourselves in a more robust and fertile environment for basic, translational, and clinical research collaboration that offers the hope of a cure in most (if not all) leukemias within our professional lifetime and provides the opportunity to harness that knowledge to minimize therapy, improve safety, and enhance efficacy.

AUTHOR CONTRIBUTIONS

Hagop M. Kantarjian: Conceptualization; supervision; funding acquisition; project administration; writing—original draft; and writing—review and editing. Gautam Borthakur: Writing—review and editing. Naval Daver: Writing—review and editing. Courtney DiNardo: Writing—review and editing. Guillermo Garcia‐Manero: Writing—review and editing. Ghayas Issa: Writing—review and editing. Elias Jabbour: Writing—review and editing. Nitin Jain: Writing—review and editing. Tapan Kadia: Writing—review and editing. Sanam Loghavi: Writing—review and editing. Farhad Ravandi: Writing—review and editing. Guilin Tang: Writing—review and editing. Mary Alma Welch: Writing—review and editing. William Wierda: Writing—review and editing.

CONFLICT OF INTEREST STATEMENT

Hagop M. Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, Immunogen, Jazz, Novartis, Pfizer; and honoraria from Amgen, Stemline, and KAHR outside the submitted work. Gautam Borthakur reports research support and honoraria from Astex, Aptevo, Bio Ascend, Bristol Myers Squibb Company, Epigentix, Molecular Partners, Nkarta, Novartis, Pacylex, and Treadwell Therapeutics; and personal/consulting fees from AbbVie, PPD Development, and Lava Therapeutics outside the submitted work. Naval Daver reports grants/research funding from AbbVie, Amgen, Astellas Pharma, Bristol Myers Squibb Company, Daiichi Sankyo Company, FATE Therapeutics, Pfizer Inc., Gilead Sciences Inc., Servier Pharmaceuticals LLC, Genentech USA Inc., ImmunoGen, Trillium, Hanmi, Trovagene, Novimmune, Glycomimetics, and Kite Pharma Inc.; and personal/consulting fees from Daiichi Sankyo Company, Bristol Myers Squibb Company, Pfizer Inc., Gilead Sciences Inc., Servier Pharmaceuticals LLC, Genentech, Astellas Pharma, AbbVie, Trillium, Arog Pharmaceuticals, Amgen, Novartis, Jazz Pharmaceuticals, Celgene, Syndax, Shattuck Labs, Agios Pharmaceuticals, Kite Pharma Inc., and Stemline/Menarini outside the submitted work. Courtney DiNardo reports personal/consulting or advisory fees from AbbVie, Amgen, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb Company, Daiichi Sankyo Company, Genmab, GlaxoSmithKline, Jazz Pharmaceuticals, Molecular Partners, Notable Labs, Rigel Pharmaceuticals Inc., Ryvu, Schrodinger, and Servier Pharmaceuticals LLC; and data and safety monitoring for Genmab outside the submitted work. Guillermo Garcia‐Manero reports research support from AbbVie, Astex, Bristol Myers Squibb Company, Chordia, Curis, Genentech, Novartis, Rigel, and Zentalis; and honoraria from Astex, Curis, and Bristol Myers Squibb Company outside the submitted work. Ghayas Issa reports research funding from Celgene, Merck, Kura Oncology, Cullinan Oncology, Syndax, Astex, Novartis, Pupil Bio, Sumitomo, Daiichi Sankyo Company, and Crossbow; personal/consulting or advisory fees from AbbVie, Novartis, Sanofi, AstraZeneca, Syndax, Kura Oncology, Biostate, and Crossbow; service on a scientific advisory board for Pupil Bio and Biostate; and data and safety monitoring for Novartis outside the submitted work. Elias Jabbour reports research grants from Adaptive Biotechnologies, Ascentage, AbbVie, Takeda, Pfizer, ASTX, Terns Pharmaceuticals, Bristol Myers Squibb Company, Johnson & Johnson, Shenzhen TargetRx, Novartis, and Amgen Pharmaceuticals; and honoraria from Adaptive Biotechnologies, Ascentage, Takeda, Genentech, AbbVie, Syndax, Daiichi Sankyo Company, Pfizer, Novartis, and Amgen outside the submitted work. Nitin Jain reports grants/contracts or research funding from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene USA Inc., Bristol Myers Squibb Company, Carna Biosciences, Cellectis, Eli Lilly and Company, Fate Therapeutics, Genentech, Gilead Sciences Inc., Kisoji Biotechnology, Kite, Mingsight, Newave, Novartis, Pharmacyclics LLC (an AbbVie company), Precision Biosciences, Sana Biotechnology, Takeda Oncology, and Triarm Therapeutics; personal fees/honoraria from AbbVie, Adaptive Biotechnologies Corporation, AstraZeneca, BeiGene USA Inc., Autolus, Bristol Myers Squibb Company, Cellectis, Eli Lilly and Company, Genentech, Gilead Sciences Inc., Janssen, Kite, Novalgen, Nurix, Precision Biosciences, and Takeda Oncology; and travel support from Pharmacyclics LLC (an AbbVie Company) outside the submitted work. Tapan Kadia reports grants/contracts or research funding from Glycomimetics, Regeneron, Abcuro, DrenBio, Incyte, Cellenkos, AbbVie, Amgen, Bristol Myers Squibb Company, Genentech, Incite Corporation, Jazz Pharmaceuticals, Pfizer, Pulmotech, Sellas, Ascentage Pharma, Astellas, Astex Pharma, AstraZeneca, Cyclacel, Iterion, and Delta‐Fly; and personal/consulting fees from DrenBio, AbbVie, Bristol Myers Squibb, Genentech, Jazz, Sellas, Novartis, Agios Pharmaceuticals Inc., Daiichi Sankyo Company, Servier Pharmaceuticals LLC, Pinot Bio, and Delta‐Fly outside the submitted work. Sanam Loghavi reports grants/contracts or research funding from Astellas Pharma and Amgen; and personal/consulting fees from Aptitude Health, AbbVie, Bristol Myers Squibb Company, Cogen, Daiichi Sankyo Company, Kura Oncology, Qiagen Inc., Recordati Rare Diseases Inc., Servier Affaires Medicales, Syndax, and Tempus AI outside the submitted work. Farhad Ravandi reports grants/contracts or research funding from AbbVie, Amgen, Astex, Bristol Myers Squibb Company, Macrogenics, Orsenix, Prelude, Taiho Pharmaceutical, and Xencor; personal/consulting fees from AbbVie, Agios Pharmaceuticals, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb Company, Celgene Corporation, the Novartis Foundation, Orsenix, and Taiho Pharmaceutical; and support for other professional activities from Celgene Corporation outside the submitted work. William Wierda reports grants/contracts research from AbbVie, Acerta Pharma, Bristol Myers Squibb Company, Cyclacel Pharmaceuticals, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Biotech, Juno Therapeutics, Kite, Loxo Oncology, Novartis, Oncternal Therapeutics, Pharmacyclics, Nurix Therapeutics, Numab Therapeutics, and BeiGene outside the submitted work. The remaining authors disclosed no conflicts of interest.

Kantarjian HM, Borthakur G, Daver N, et al. A tour of leukemia progress in 2025, viewed through the MD Anderson leukemia research lens. Cancer. 2025;e70113. doi: 10.1002/cncr.70113