The Cure of Leukemia Through the Optimist’s Prism

Abstract

Progress is occurring at a dizzying rate across all leukemias. Since our review of the topic in CANCER in 2018, numerous discoveries have happened that improved the therapy and outcome of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab ( 10-year survival 90+%). Acute promyelocytic leukemia is curable at a rate of 80%−90% with a non-chemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate in core-binding factor acute myeloid leukemia (AML) is 75+% with fludarabine, high dose cytarabine and gemtuzumab ozogamycin. Survival in chronic myeloid leukemia is close to that of the age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors ( TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may be now potentially curable with a finite duration of therapy with Bruton tyrosine kinase ( BTK) inhibitors and venetoclax. The estimated 5-year survival in Philadelphia-chromosome positive acute lymphocytic leukemia( ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third generation BRC-ABL1 TKI; and more recent non-chemotherapy regimens utilizing dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 ( blinatumomab) and CD22 ( Inotuzumab ) to chemotherapy. Several recent drug discoveries ( venetoclax, FLT3 and IDH inhibitors, oral hypomethylating agents) are also improving the outcomes in younger and older patients with AML, and those with higher risk myelodysplastic syndrome.

Precis:

Major progress is occurring at a very rapid pace in leukemia. This review summarizes the important recent discoveries in these disorders.

INTRODUCTION

Progress in leukemia research and therapy is advancing at a dizzying pace. Summaries published even as late as 2014 and 2018 by experts do not capture the exciting discoveries that have occurred. (1,2) Since then, novel therapeutic breakthroughs have impacted several leukemia subsets. Chronic lymphocytic leukemia (CLL), still reported as “incurable” in the medical textbooks, may now be potentially curable with a finite duration of combination targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors with venetoclax. (3,4) In acute lymphoblastic leukemia (ALL) the introduction of highly effective antibodies targeting the clusters of differentiation (CD) CD19, CD20, and CD22 into chemotherapy combinations is changing dramatically the treatment and prognosis of the disease. In the subset of Philadelphia-chromosome (Ph)-positive ALL, incurable before 2000 except with allogeneic stem cell transplantation (SCT), treatment with combination chemotherapy regimens and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are producing estimated 5- to 8-year survival rates of 70+%. (5) Even more promising in ALL are the non-chemotherapy regimens (similar to all-trans retinoic acid plus arsenic trioxide regimen in acute promyelocytic leukemia [APL]) that combine next-generation BCR-ABL1 TKIs with anti-ALL antibodies. (6) In acute myeloid leukemia (AML), the discovery of the efficacy of several targeted modalities (venetoclax; FLT3 and IDH inhibitors), and the benefit of maintenance therapy followed by incorporating these approaches into the standard of care, are improving outcome rapidly. (7,8) The progress across leukemias is summarized in Table1 (discussed in detail throughout the review)

Table 1.

Leukemia Progress in 2021

Disease	Potential Current/ ProposedFuture Therapies	% Cure/5–10-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	fludarabine, cytarabine, granulocyte colony-stimulating factor, and gemtuzumab ozogamicin +/−idarubicin (FLAG-GO +/− IDA)	80–90
Acute myeloid leukemia-younger/fit	FLAG-IDA- venetoclax; CLIA-venetoclax; FLT3 or IDH inhibitors if indicated; maintenance therapy with oral azacitidine/decitabine/HMAs with venetoclax or FLT3/IDH inhibitors ; new role of menin inhibitors	50–60+
Acute myeloid leukemia-older/unfit (also ?complex karyotype, TP53-mutated, MECOM,others)	Low-intensity triple nucleosides ( cladribine-cytarabine-HMAs + venetoclax; HMAs+ venetoclax + addition of other targeted therapies e.g. FLT3/IDH inhibitors; decitabine 10 days + venetoclax; oral decitabine + venetoclax	40–50?
Acute lymphoblastic leukemia (ALL) <60 years	Hyper-CVAD + CD19/CD22/CD20 targeted antibodies	60–70
ALL older, 60+ years	Mini CVD-inotuzumab-blinatumomab	50
Ph-positive ALL	Hyper-CVAD-ponatinib; ponatinib-blinatumomab	70–80?
Chronic myeloid leukemia	BCR-ABL1 tyrosine kinase inhibitors ( imatinib, dasatinib, bosutinib, nilotinib, ponatinib); omacetaxine; allogeneic SCT; others ( cytarabine, HMAs, hudroxyurea)	85–90
Chronic lymphocytic leukemia	Ibrutinib/other Bruton tyrosine kinase inhibitors (acalabutinib, zanubrutinib, pirtobrutinib [LOXO 305] )+ venetoclax +/− CD20 antibodies	80–90+ ?
Myelodysplastic syndrome (higher risk)	Parenteral HMAs, oral HMAs+ venetoclax; others	40+

GO = gentuzumab ozogamicin; HMAs = hypomethylating agents; FLAGIDA = fludarabine, high dose cytarabine, idarubicin; CLIA = cladribine, high dose cytarabine, idarubicin; Hyper-CVAD = hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone

See text for details of current and proposed future therapies

The timely dissemination of this knowledge and its applications into the medical and cancer community practices is critical, since the subtle and not-so-subtle therapeutic benefits in these rare cancers, now divided into even smaller and smaller subsets, may go unnoticed by medical practitioners not accustomed to treating patients with leukemia. Herein we update developments that have emerged since our 2018 review and provide a high-level overview of progress in leukemia.

In 2018, we divided the leukemias into 3 categories. (2) The-easy-to-cure leukemias ( referred to later as “easy leukemias”) were four subsets in which progress was substantial, therapy close to ideal, and 5- or 10-year survival rates were above 70%−80+%: hairy cell leukemia (HCL), APL, core-binding factor (CBF) AML, and chronic myeloid leukemia (CML). Today, we can probably shift three of the previous intermediate-cure potential leukemias (referred to later as “intermediate leukemias”) into the easy column: CLL and, perhaps soon with maturing data, younger ALL (< 60 years old), and Ph-positive ALL. The intermediate leukemias (now excluding the three previous entities) include those with estimated 5-year survival rates between 30% and 70%: older ALL and, perhaps soon, younger non-APL/non-CBF AML (age < 60 years), with particular cytogenetic-molecular exclusions. The more-difficult-to cure leukemias ( or “more difficult leukemias”) are ones where the estimated 5-year survival rate is still less than 30%: older AML and several other subtypes of AML -- complex or adverse karyotype, adverse mutations, TP53 mutations, mixed-lineage leukemia (MLL), therapy-related or secondary AML evolving from myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and the related higher-risk MDS.

THE EASY LEUKEMIAS

Hairy Cell Leukemia

Observation, supportive care, splenectomy, and first-generation chemotherapy agents were the mainstays of therapy in HCL until 1983, when interferon alpha was found to be effective. (9) In retrospect, this discovery seems a minor breakthrough, but it helped establish the potential role of non-cytotoxic immunotherapy in the treatment of cancer. This was followed by the discovery of the efficacy of the adenosine nucleoside analogs cladribine (CDA) and pentostatin, which changed the outlook in HCL. (10,11) These therapies yielded response rates of 80%−100%, and 10-year survival rates of 70%. Still, 50% of patients relapsed after a median time of 5 to 10 years.

In 2003, rituximab, a CD20 monoclonal antibody, was found to be effective in HCL. (12) This resulted in a study of the sequential administration of CDA and rituximab: CDA 5.6 mg/m2 intravenously (IV) over 2 hours daily x 5 (with growth factor support and antibiotics); following recovery of counts ( about one month later), rituximab 375 mg/m2 is given weekly for eight doses. (13,14) In an update of the results in newly diagnosed patients treated with this regimen, the 10-year failure-free survival rate was 95% (Figure 1; unpublished). In a randomized study, 68 patients received the combination of concurrent CDA plus rituximab versus CDA alone (with rituximab given at 6 months or later upon detection of measurable residual disease [MRD]). (15). The MRD-free CR rates were 97% with the concomitant combination versus 24% with the delayed-rituximab regimen (p<.0001). At a median follow-up of 96 months, 94% versus 12% of patients remained MRD-free. The CDA plus rituximab combination in HCL is a hard-to-beat standard of care, except for possibly replacing intravenous CDA with an oral formulation, for ease of administration. Other strategies targeting BRAF mutations with BRAF inhibitors in combination with rituximab show promising activity. (16) In HCL refractory to these modalities (a rarity today), investigating agents that target CD19 (blinatumomab), CD22 (inotuzumab) and CD20 (bi-specific T-cell engagers) are of interest.

Figure 1.

Survival and Progression-free survival in hairy cell leukemia with cladribine followed by rituximab (MD Anderson experience). All 4 deaths unrelated to disease or treatment (1 old age 96 years; 1 suicide; 2 other cancers)

Acute Promyelocytic Leukemia

About 5%−10% of AML cases are APL. The disease hallmarks are the cytogenetic abnormality of the translocation between chromosomes 15 and 17 -- t (15; 17) (q22; q12) -- and the resulting PML-RAR alpha molecular abnormality. (17,18) Anthracyclines were the first cytotoxic agents shown to cure 30% of patients. (19) The added benefits of cytarabine and of maintenance therapy were modest. With anthracycline-cytarabine combinations, the cure rate in APL was about 40%. A third of patients died during induction from complications of disseminated intravascular coagulopathy (DIC). (20,21)

Chinese investigators reported on the high efficacy of all-trans retinoic acid (ATRA) in APL in 1988, and of arsenicals in 1997. (22,23) Single arm and randomized trials then demonstrated that the addition of ATRA or arsenic trioxide to anthracyclines improved the 5-year survival rate to 80+%. This established the anthracyclines-ATRA programs (AIDA regimen = ATRA + IDA) as a new standard of care until 2012. (24) Studies from China, India and Iran reported on the high efficacy of both ATRA and intravenous arsenic trioxide as single agents in frontline APL therapy, with single agent arsenic trioxide resulting in 5-year survival rates of 60+%. (25–27) Based on the survival data, these studies suggested that arsenic trioxide was the single most active agent against APL, followed by gemtuzumab ozogamicin (GO), ATRA, and anthracyclines. (28)

In 2001, we cautiously began to explore the non-chemotherapy regimen of ATRA + arsenic trioxide as salvage, then in frontline APL therapy. GO (6–9 mg/m² × 1) was added in high-risk APL (WBC> 10×10⁹/L at presentation or during induction) and for persistent molecular disease (PML-RAR alpha positivity by polymerase chain reaction [PCR] after at least 2–3 months in remission). ATRA is given as 45 mg/m2 orally daily (in two divided doses during induction. Once in complete remission (CR), ATRA continues 2 weeks on and two weeks off for a total of 9 months. Arsenic trioxide is given as 0.15 mg/kg (about 10 mg fixed dose) daily during induction. Once in CR, it continues daily x 5 (omitted on weekends), weekly x 4, every other months, for a total of four additional courses ( equal about 80 doses of maintenance; total about 110 doses of induction plus maintenance). This regimen produced a CR rate of 90% and five-year survival rates above 80%. (29–31) Randomized trials of this combination versus AIDA or similar regimens, in both higher- and lower-risk APL, confirmed the findings. (32–34) The ATRA plus arsenic trioxide regimen is now a 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 on the treatment delivery and convenience in CR. (35, 36) Monitoring for PML-RAR alpha MRD in CR should also be standard in order to direct preemptive therapy. (37)

Core-Binding Factor Leukemias

The CBF AMLs are about 10%−15% of AML cases, higher in children (20%−30%). These include AML with cytogenetic abnormalities of inversion 16 or translocation (16; 16) [inv (16) (p13.1q22), t (16;16) (p13.1; q22)] and translocation 8;21 [t (8;21) (q22; q22)]. The outcome in in this subset improved following two important therapeutic developments: high dose cytarabine and GO. (38–40) The high dose cytarabine concept was developed in the early 1980s and established as an important addition in AML consolidation, followed by the finding that more consolidation courses were better. Four courses of high-dose cytarabine consolidations were associated with superior survival compared with 1–3 courses in both CBF subsets: 5-year survival rates 50% versus 30%−40%. (38) Fludarabine-cytarabine regimens produced better outcomes in retrospective analyses of the CBF results.(41) In the MRC randomized trials, Burnett and colleagues reported that patients with CBF AML who were able to complete two courses of fludarabine-high dose cytarabine-idarubicin followed by two courses of high dose cytarabine ( difficult regimen to deliver; not on intention-to-treat analysis) had a 5-year survival rate of 95% (63% for intermediate-risk cytogenetics). (42) In a meta-analysis of 5 randomized trials, the addition of GO was associated with improved survival in patients with favorable and intermediate cytogenetic risk groups. In the favorable risk group of CBF AML, the 5-year survival rates were 75% versus 50% (p<0.0001). (40) At MD Anderson, the combination of fludarabine-high dose cytarabine-GO (FLAG-GO) resulted in a 5-year survival rates of 80% in younger patients and 55% in older patients (> 60 years of age). (20,21,43) GO is now part of the standard of care in CBF AML. Persistent MRD in CBF AML is associated with worse outcome. (44,45) Therefore, patients with residual molecular disease after 4–6 cycles of chemotherapy may be considered for allogeneic SCT or offered additional therapy in order to achieve MRD negative status. Frequent mutation in CBF AML include FLT3, C-KIT and RAS. C-KIT mutations were associated with adverse outcomes in some trials, with suggestions of benefit from adding c-kit inhibitors such as dasatinib, midostaurin or avapritinib.(20, 21, 46,47) In our studies using FLAG-GO +/− idarubicin, C-KIT and other mutations were not adverse, suggesting the potential benefit of such regimens.

Chronic Myeloid Leukemia

The genetic-molecular hallmark in CML is the Philadelphia (Ph) chromosome abnormality, characterized by the translocation between the long arms of chromosomes 9 and 22, t (9; 22) (q34; q11), and the resulting BCR-ABL1 fusion gene that causes CML. (48–51)

Before 2000, treatment options in Ph-positive CML included hydroxyurea, busulfan and interferon alpha, resulting in median survival rates of 3 to 6 years and 10-year survival rates of 10%−20%. Interferon alpha therapy provided complete cytogenetic response (CG CR) rates of 10%−30% and improved survival compared with hydroxyurea-busulfan therapy. Patients achieving a CG CR had 10-year survival rates of 50+%, attesting to the potential benefit of achieving minimal disease status in order to improve survival. Allogeneic SCT was increasingly offered to eligible patients beginning in the early 1980s and was associated with 5-year survival rates of 40%−60%. (48–51)

Once the CML molecular events were unraveled, and their causal association to the development of CML-like disease in animal models confirmed, research focused on developing BCR-ABL1 TKIs. The first was imatinib mesylate, which transformed the treatment and prognosis of CML and served as a paradigm for the development of targeted therapies in other cancers. For the first time, frontline therapy with imatinib produced a cumulative incidence of CG CR approaching 90%. The cumulative incidence of deep molecular response (DMR; defined as a 4–4.5 log reduction in the BCR-ABL1 transcripts on the International Scale [IS], or BCR-ABL1 transcript levels <0.01%−0.0032%), was 60%−80% at 5 years. Imatinib therapy also was associated with the reduction of annual mortality from 10%−20% to 2% or less. (52,53) The estimated 10-year survival rate was 75%−80+% with all-cause mortality events, and 90% in the case of CML- or treatment-associated mortality events (Figure 2). Compared with an age-matched normal population, patients with CML on optimal TKI therapy had an annual mortality from CML of 0.5% or less. (54) Today, with optimal TKI management, CML is “functionally” curable. Patients are expected to 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.

Figure 2.

Survival in chronic myeloid leukemia at MD Anderson Cancer Center over 5 decades

Five TKIs are approved by the Food and Drug Administration (FDA) for the treatment of Ph-positive CML, four of them as frontline therapy: imatinib, dasatinib, nilotinib, bosutinib. (52,53,55–59) The fifth, ponatinib, a third generation TKI, is approved in resistant disease with a T315I mutation, or post failure with at least two other TKIs. (58) Several reviews have detailed the management of CML (48–51); we will emphasize a few lesser known but important points.

The aims of therapy are 1) normalization of survival and 2) achievement of a “treatment-free remission” (TFR) status whenever possible. For normalization of survival, frontline therapy with imatinib, dasatinib, nilotinib or bosutinib achieves the goal. If imatinib therapy is selected, then careful monitoring and change of therapy at first evidence of resistant disease (loss of CG CR; BCR-ABL1 transcripts [IS]> 1% or > 0.2–0.5% consistently) is critical. The choice of salvage therapy is guided by an evaluation of possible mutations at the ABL kinase domain site at the time resistance is identified, and also by the patient age and comorbidities. The approved frontline dose schedules of TKIs are: imatinib 400 mg daily; dasatinib 100 mg daily; nilotinib 300 mg twice daily on an empty stomach; bosutinib 400 mg daily. Dasatinib 50 mg daily is as effective as 100 mg daily in the frontline setting and significantly less toxic. (59) In patients who achieved a deep response, such as CG CR or major molecular /deep molecular response ( MMR = BCR-ABL1 transcripts [IS] < 0.1%; DMR = BCR-ABL1 transcripts [IS] < 0.01%) but who experience significant side effects, the doses can be reduced to as low as: imatinib 100–200 mg daily; dasatinib 20 mg daily; bosutinib 100–200 mg daily; nilotinib 150–200 mg daily. For salvage therapy, the dose schedules are: dasatinib 100 mg daily; nilotinib 400 mg twice daily; bosutinib 500 mg daily. Ponatinib is FDA approved at a dose of 45 mg daily but can be associated with serious side effects. Recent studies have shown that ponatinib 45 mg daily is superior to lower doses in T315I-mutated CML, but that 30 mg is equivalent in non-T315I-mutated cases, and that the dose can be reduced to 15 mg daily once a CG CR is achieved (BCR-ABL1 transcripts [IS] < 1%). (60,61)

The cost of TKIs is an important consideration. Imatinib is now available in safe and effective generic formulations, which are significantly less expensive. Dasatinib is also available in generic formulations in some countries. In an average patient, imatinib may be a reasonable frontline option. However, newer generation TKIs may be favored as frontline therapy in some subgroups: younger patients in whom achieving TFR is a consideration (discussed later); patients with high risk disease (e.g. high risk Sokal score). Dasatinib 50 mg daily is the preferred frontline therapy at our institution. Nilotinib is commonly used as frontline therapy in certain geographic areas (e.g. some European countries, Australia).

The side effects of TKIs are well known, but some require emphasis. For imatinib, notable side effects 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. Myelosuppression (10%−20%), pleural effusions (10%−15%) and occasional pulmonary hypertension (1%−2%) can occur with dasatinib 100 mg daily, much less with 50 mg daily. Nilotinib therapy may be associated with hyperglycemia (10%−15%), exacerbation of diabetes (5%−10%), pancreatitis (1%−3%) and vasospastic/vaso-occlusive disease (cumulative incidence 15%−25% at 10 years with 300 mg twice daily, 30+% with 400 mg twice daily; noted more recently with long-term follow up). Notable side effects of bosutinib include diarrhea (10%−30%, usually mild-moderate, early and self-limited), which can rarely progress into 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. Rare neurotoxicity mimicking worsening parkinsonism, dementia, and “Lewy body dementia-like” have been rarely observed and reverse slowly several months after treatment discontinuation.

While achievement of CG CR is considered the sine qua non for survival prolongation, and lack of its achievement with TKIs as an indication for allogeneic SCT, this may not be possible in some patients. If they are older (65–70+ years old), they may remain in chronic phase in some form of partial cytogenetic response or even 100% Ph-positive, and still live their normal lives. In select cases, this may be preferred over resorting to a potentially curative allogeneic SCT with its associated morbidities and mortality.

Prior to the development of TKIs, allogeneic SCT was the only curative modality for CML and was considered frontline therapy. Today, it is used for salvage therapy in patients who are resistant to at least one second generation TKI (dasatinib, bosutinib, nilotinib), and those who develop T315I-mutated disease. These patients can be also treated with ponatinib. This gives patients the option to continue oral therapy if a good (cytogenetic) response is obtained, or to move to allogeneic SCT because of cost issues, toxicities, or patient/physician choice. Other reviews cover the details of CML therapy, the endpoints of treatment (CG CR, survival, TFR), optimal monitoring, dose schedules and management of toxicities. (48–51)

Achieving a TFR status is particularly important in younger patients, to avoid lifetime therapy. Discontinuing therapy after achieving DMR for 2–3 years is associated with a TFR rate of 50%−60%. (62–64) Discontinuing therapy after a durable DMR for 5+ years increases the TFR probability to 80+%. (64)

Additional third generation TKIs are under development to target T315I-mutated CML, and to improve efficacy and toxicity profiles beyond those achieved with ponatinib. These include asciminib, olverembatinib (HQP1351), vodobatinib (K0706) and others. (65–67). Asciminib is the most advanced in development and may move into earlier salvage therapy in patients without T315I mutations.

In summary, with optimal therapy, CML should be considered an indolent leukemia that is functionally (normal life with continued TKI) and molecularly curable (TFR in 30%−40% of patients) with TKI-based regimens. Future considerations are to address strategies to increase the rates of durable DMRs and TFRs and reduce TKI toxicities and cost.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is still described as incurable in medical textbooks. (68,69) This may not be the case anymore with the deciphering of its pathophysiology and the development of BTK inhibitors and venetoclax, now used in combination.

Historically, CLL was treated with alkylating agents (chlorambucil, cyclophosphamide), steroids, vincristine and others cytotoxics. These therapies did not improve survival. (70,71)

A positive trend started in the 1980s with the discovery of the efficacy of the adenosine nucleoside analogs fludarabine and cladribine. Fludarabine was developed primarily in the United States. Cladribine (both intravenous and oral) was developed in Europe. A series of single arm trials, at MD Anderson and elsewhere, and randomized trials confirmed the efficacy of fludarabine, which was later combined with cyclophosphamide (FC regimen) and rituximab (FCR or FR), leading to the potential cure of a subset of patients with the FCR regimens. (72–74) Randomized trials comparing fludarabine to chlorambucil, FC to fludarabine alone, and FCR to FC established the superiority of FCR, which became a standard of care in Europe and the United States. (75,76) Following the discovery of the activity of bendamustine and its subsequent combination with rituximab (BR), randomized studies demonstrated the superiority of FCR over BR for PFS. (77) Long-term results of FCR therapy demonstrated that, among younger/fit patients with good prognostic features (mutated immunoglobulin heavy chain gene [IgHV] and no deletion of chromosome 17p or TP53 aberration) treated with the triple therapy (about 10–20% of patients with CLL requiring therapy), the FCR regimen produced a 10-year disease-free survival rate of about 55%−60%. (72–74)

Further important advances happened in the mid-2000s, with the deciphering of the B-cell receptor (BCR)-related CLL pathophysiology and the BTK, PI3 kinase delta and other pathways related to CLL evolution, and with the understanding the significance of BCL2 signaling in prolonging CLL cell survival. Based on these findings, several small molecules were developed, including ibrutinib (BTK inhibitor), idelalisib (PI3K delta inhibitor) and venetoclax (BCL2 inhibitor). (78–81) Recent updates on the efficacy of combinations of these drugs might shatter the dogma of the incurability of CLL. It is now reasonable to suggest that CLL may be potentially curable with a finite duration of venetoclax-based doublets with CD20 antibodies or ibrutinib (or another BTK inhibitor), or with triple therapy (BTK inhibitor-venetoclax-CD20 antibody). This could replace indefinite daily therapy with a BTK inhibitor. Novel covalent BTK inhibitors (acalabrutinib, zanubrutinib) or the non-covalent BTK inhibitor pirtobrutinib (previously LOXO-305) may be less toxic and/or more potent than ibrutinib. (82–89)

In a single-arm phase 2 trial, Jain and colleagues treated 80 patients with CLL who were age 65 and older or who had adverse-risk features (deletion 17p, TP53-mutated, deletion 11q, or unmutated IGHV) with ibrutinib 420 mg daily for 3 courses, followed by the addition of venetoclax (standard weekly ramp-up to 400 mg daily) for 24 courses of combination treatment. Overall, 60 patients (75%) achieved bone marrow undetectable-MRD remission (U-MRD) as best response. After a median follow-up of 38.5 months, the 3-year progression-free survival rate was 93% and 3-year survival rate 96% (Figure 3). Among 51 patients with U-MRD status who discontinued therapy (median follow-up after treatment discontinuation of 12.4 months), eight patients had MRD recurrence. No patient had CLL progression; two had Richter transformation. (3,4) The CAPTIVATE study is a multicenter trial employing a similar strategy combining ibrutinib and venetoclax for 1 year, followed by randomization to different arms based on MRD status. (87) After 12 cycles of combination therapy, the bone marrow U-MRD rate was 68% and the peripheral blood U-MRD rate was 75%. Additional ongoing trials are evaluating the combination of BTK inhibitors with venetoclax, with or without CD20 antibodies, both in frontline and relapsed CLL. (88,89)

Figure 3.

Survival in chronic lymphocytic leukemia with ibrutinib-venetoclax

Other studies will compare the efficacy and safety of doublet or triplet regimens containing BTK inhibitors, venetoclax and CD20 antibodies; different durations of therapy; side-effects; and costs. These will hopefully refine the management of CLL, which has now been transformed from an incurable leukemia to one potentially functionally curable, or even molecularly curable, with a finite duration of therapy.

Acute Lymphoblastic Leukemia in Younger Patients (Age 15–60 Years); Ph-positive ALL

The cure in children with ALL is 80% or more with regimens optimized over four decades, delivered over 2.5 to 3 years, and combining about 15 cytotoxic drugs in intensive treatments that include induction, intensifications, maintenance and central nervous system (CNS) prophylaxis.(90) The same regimens given to adults with ALL resulted in cure rates of only 50% in patients younger than 60 years and of 10%−20% in older patients. (91–93)

In the early 1980s, there was a shift away from the principles adopted in pediatric ALL for the adult treatments, essentially to resemble more the AML regimens. This included reduction of the intensity of the non-myelosuppressive drugs (steroids, vincristine, asparaginase), a shorter duration of maintenance with POMP (6-mercaptopurine, vincristine, methotrexate, prednisone), and reliance on early implementation of autologous and allogeneic SCT in first CR. Retrospective studies comparing the pediatric-inspired regimens to the “modified” adult ALL regimens in adolescents and young adults (up to age 39 and referred to as AYAs) indicated the superiority of the pediatric regimens. Prospective studies using similar pediatric-inspired regimens in adults up to the age of 40 years reported 5-year survival rates of 60%−65%. (94, 95) Because of the inclusion of asparaginase in these programs, toxicities limited their use in older patients.

Adult ALL regimens that kept the principles of pediatric regimens (intensive induction-consolidation-intensification-maintenance; intrathecal CNS prophylaxis) have resulted in CR rates of 90+%, but cure rates plateaued at 50%−60% in patients up to 60 years old. This was the case with the Hyper-CVAD regimen (hyper-fractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine). (96–98)

The 30% to 40% difference in outcome between pediatric and adult patients on similar regimens is largely attributable to four cytogenetic-molecular subsets with vastly different incidences and prognoses in pediatric versus adult ALL. (99) The first two subsets are hyperdiploid karyotype and ETV6-RUNX1 translocations; these have favorable prognoses and constitute about 50% of childhood ALL but less than 5%−7% of adult ALL. The other two subsets are Ph-positive (15% to 25% of adults and 5% of children; historically adverse but not anymore) and the recently described “Ph-like ALL” ( 15%−25% of adults and 8%−10% of children; historically adverse but perhaps not anymore with the new combined chemotherapy-novel antibody regimens, discussed later). The latter two historically unfavorable subsets combined represent 30%−50% of adult ALL and < 15% of childhood ALL. Among Hispanic adults with ALL in the United States, Ph-positive disease constitutes 25%, and Ph-like ALL about another 40%−50% of cases. Ph-like disease presents with a molecular profile like Ph-positive ALL, but without the characteristic t (9;22) cytogenetic abnormality or the BCR-ABL1 fusion oncogene. About 80% of Ph-like ALLs have overexpression of CRLF2 (half with JAK mutations; unfavorable and not responsive to JAK2 inhibitors but perhaps sensitive to the novel antibodies and to venetoclax). The other 20% have translocations involving ABL1 or others responsive to regimens that include BCR-ABL1 TKIs. (100–103)

It is important to note that, even within well-defined subsets, childhood ALL remains much more responsive to therapy. In the era preceding BCR-ABL1 TKIs, children with Ph-positive ALL had a 5-year survival rate of 35% with chemotherapy, in contrast to <10% in adults. The recent experiences with novel antibodies and chimeric antigen receptor T (CART) cellular therapy also show significantly better results in children than adults. (104–109). For instance, chemotherapy regimens in adult ALL salvage 1 are associated with CR rates of <20%−40% and 2-year survival of <5%−10%, while single-agent blinatumomab therapy in adult refractory-relapsed (R-R) ALL is associated with a 2–3-year survival of 25%. (106,107) In contrast, children in ALL salvage 1 treated with two courses of chemotherapy and then randomized (if blasts <25% or MRD-positive) to blinatumomab versus chemotherapy had a 2-year survival rate of 79% with blinatumomab and 59% with chemotherapy. (108,109) With CART therapy in salvage, the 2-year survival rates are 50%−60% in children versus <20% in adults. (104,105)

Progress in adult ALL therapy since the early 2000s is the result of several factors: 1) The development of the Hyper-CVAD regimen in 1992 and the use of pediatric regimens (since the late 2000s) in the AYA group. (94, 95, 110) Of note, the pediatric regimens use intensified asparaginase-vincristine-steroids, and asparaginase can be associated with serious toxicities: liver dysfunction in 20%; thrombosis in 10%; pancreatitis in 5%−10%; disseminated intravascular coagulopathy and hip necrosis in 5%−10%. Such regimens are poorly tolerated in patients older than 40 years. The Hyper-CVAD regimen can be delivered with an acceptable toxicity profile in adults up to the age of 60 years, and, with modifications (mini-CVD regimen combined with antibodies), to older patients. In addition, third generation TKIs and novel antibodies can be incorporated in it safely. 2) The addition of BCR-ABL1 TKIs into regimens in Ph-positive ALL, and, more recently, the substitution of blinatumomab in place of intensive chemotherapy. (5, 6, 111–116) 3) The addition of rituximab and other CD20 antibodies (e.g. ofatumumab) to chemotherapy in CD20-positive ALL. (98,117–120) 4) The discovery of the high efficacy of antibody-drug conjugates (ADCs) targeting CD22 (inotuzumab ozogamicin, conjugated to calicheamicin) and of bispecific T-cell engaging (BiTE) antibody constructs targeting CD19 (blinatumomab, targets CD3 and CD19). (106,107,121–123) 5) The development of the highly active CD19 CART therapy in ALL salvage. (104,105). 6) The recognition of the adverse prognostic significance of MRD-positive disease in CR and the implementation of remedial strategies in such patients (currently blinatumomab and, perhaps in the future, inotuzumab and other antibodies, CARTs, or combined-modality strategies including sequential allogeneic SCT). (124,125)

Frontline Therapy of Younger ALL

Following the adoption in 1992 of the Hyper-CVAD regimen at our institution, and because of the expression of CD20 on the surface of Burkitt and pre-B-ALL cells, in 2000 we added rituximab to the regimens in those subtypes. (117,118) This addition produced better results than the historical experience with Hyper-CVAD alone, even though single agent rituximab has no activity in ALL. Randomized trials in Burkitt disease and in adult ALL confirmed the benefit. (119,120) After a 2006–2012 Hyper-CVAD therapeutic lull (when we used the pediatric-inspired augmented BFM regimen in patients up to the age of 40 and showed Hyper-CVAD was equivalent), (96, 97) we resumed the use of Hyper-CVAD but replaced rituximab with ofatumumab, (98) and demonstrated the ofatumomab combination to be superior. (126) At a median follow-up of 44 months, the median relapse-free survival with the Hyper-CVAD-ofatumumab regimen was 52 months and the median OS was not reached. The 4-year relapse-free survival and overall survival rates and were 60% and 68%, respectively. For patients < 40 years old, the 4-year survival rate was 74%. (98,126)

Major breakthroughs came around 2010 when Topp and the German investigators developed blinatumomab in R-R ALL and showed its remarkable efficacy (121), while inotuzumab was developed on an institutional IND at MD Anderson and proved to be highly efficacious. (122,123) Subsequent randomized trials in refractory relapsed ALL confirmed the significant superiority of both blinatumomab and inotuzumab compared with standard of care intensive chemotherapy. (106,107) However, considering their costs and modest survival benefits, the antibody therapies did not offer a good “treatment value” as single agents (in contrast to the experiences in childhood refractory relapsed ALL) (108,109). This quickly led to the exploration of combinations of the antibodies with mini-Hyper-CVD in both refractory relapsed and frontline older ALL, followed by the investigation, beginning in 2015, of their combination with Hyper-CVAD (first blinatumomab, and later Inotuzumab), in patients up to age 60 years. The preliminary experience is encouraging. In the first 38 patients treated, the CR rate was 100%, the MRD-negativity rate was 97%, and the estimated 3-year survival was 80%. (127) If the data continue to mature with similar results in a larger cohort of patients, this may offer a new ALL therapeutic strategy.

Future regimens may include ADCs or CD20-directed BiTEs rather than CD20 unconjugated antibodies. Such BiTEs are showing encouraging activity as single agents in lymphomas. (128,129) Trispecific T-cell engagers (TriTEs) targeting both CD20 and CD19 or CD22 (in addition to CD3) are potentially exciting. (130) CART cellular therapy with autologous cells or allogeneic off-the-shelf products, repeated infusions, NK-cell-directed therapies and products targeting CD19 and CD22 and/or CD20 simultaneously should be explored, as well as using CARTs in first CR for MRD positivity or as consolidation therapy. (131,132)

Monitoring of MRD is now standard of care, but next generation sequencing (NGS) techniques that detect levels as low as <10⁻⁶ may better predict patient outcomes, direct changes of therapy and allow tailoring the duration of therapy in individual patients based on the NGS MRD status in CR. Improved survival results in younger patients (<60 years) with ALL over the past four decade are shown in Figure 4.

Figure 4.

Survival in younger patients with acute lymphoblastic leukemia (MD Anderson data)

Frontline Therapy of Ph-Positive ALL

Before 2000, pediatric patients with Ph-positive ALL treated with intensive chemotherapy had 5-year survival of 30%−35%. In adult Ph-positive disease, despite a CR rate of 80%−90% with chemotherapy, the cure rate was less than 10%, and 35%−40% with allogeneic SCT in first CR. Together with ALL with translocation 11q23 ( mixed-lineage leukemia; MLL), Ph-positive disease was the worst of the subsets. (91–93)

The addition of imatinib to chemotherapy in 2000 altered the course of Ph-positive ALL, with 5-year survival rates of 40%. (111) The use of second generation TKIs (dasatinib and nilotinib) in place of imatinib in single-arm and randomized trials improved the results further.(112,113) In a randomized trial of intensive chemotherapy plus dasatinib versus imatinib in 189 children with Ph-positive ALL, dasatinib therapy was associated with a 4-year survival rate of 88% versus 69% with imatinib ( p=0.04), and with significant reductions in the incidences of relapse (20% versus 34%; p= 0.01) and CNS disease (2.7% versus 8.4%; p=0.06). (133) In the SWOG trial of Hyper-CVAD + dasatinib in 97 patients treated, the CR rate was 88%, and the 3-year survival rate was 69%. The outcome was better among the 42% of patients who underwent allogeneic SCT in first CR. (113)

Because of the observation in 2010 that some relapses were due to T315I-mutated disease, we began investigating Hyper-CVAD plus the third generation TKI ponatinib (114). In addition, as patients were living longer, CNS relapses were occurring more frequently (in 10%) despite 8 intrathecal doses of CNS prophylactic chemotherapy. An increase to 12 doses of intrathecal treatment for patients with Ph-positive disease appears to have eliminated the risk of CNS relapse. Also, because the approved ponatinib dose of 45 mg daily is associated with increased incidence of cardiovascular toxicities, we reduced the dose to 30 mg daily once a CG CR was achieved, and to 15 mg daily once a DMR was achieved (BCR-ABL1 transcripts < 0.01%). Patients with persistent disease (PCR > 0.1% 3–6 months into CR) were offered allogeneic SCT. Among 86 patients treated (median age 47 years; range 39–61 years), the CR rate was 100%, the flow-cytometry MRD negativity rate was 99%, the PCR-negativity rate was 84%, and the 6-year survival was 76%. (5) Thus, with effective targeted therapy, Ph-positive ALL was transformed from one of the most unfavorable ALL subsets to one of the most favorable (Figure 5). Ribera and the Spanish investigators conducted a similar study using intensive chemotherapy and ponatinib but utilized allogeneic SCT in first CR as the curative strategy. Among 30 patients treated (median age 50 years; range 20–59 years), the CR rate was 100%, the complete molecular response rate prior to SCT was 68%, and 28/30 patients (93%) underwent SCT. The 2–2.5-year EFS rate was 91%. (134) The superiority of ponatinib in the frontline management of ALL is further supported by a meta-analysis and a propensity-matched score analysis, both showing a survival benefit with ponatinib-based regimens. (135,136)

Figure 5.

Survival in Philadelphia chromosome-positive acute lymphoblastic leukemia over 5 decades (MD Anderson data)

In Europe, several studies investigated regimens using TKIs with minimal chemotherapy in older Ph-positive ALL. The maturing data showed 5-year survival rates of 33% −46%, and heavy reliance on SCT in first CR (30%−72%). (135) A recent study of ponatinib and steroids by Martinelli and Italian investigators was promising. (137) Among 42 patients treated (median age 69 years; range 27–85 years) the CR rates was 93%, the complete molecular response rate was 46%, and the 2-year survival was 62%. Following the analyses of the subsets of refractory relapsed Ph-positive ALL treated with blinatumomab or inotuzumab versus standard of care, which showed the superiority of the targeted therapies, (138–140) Foa and Italian colleagues treated 63 patients (median age 54 years; range 24–82 years) with dasatinib 140 mg daily (along with steroids during the first month of induction), and then added blinatumomab 3 months into dasatinib therapy for at least 2 courses and up to 5 courses. They reported a response rate of 100%, a molecular response rate of 60% and a complete molecular response rate of 41%. Fifteen patients had MRD increases (6 with T315I-mutated disease), which decreased with the addition of blinatumomab. Twenty-four patients (38%) underwent allogeneic SCT. The estimated 12-month event-free survival and survival rates were 88% and 95%, respectively. (6) Maturing data of this study will be important in deciding whether Ph-positive ALL can be treated with non-chemotherapy targeted therapies, or whether chemotherapy and/or allogeneic SCT are required for cure. At MD Anderson, we initiated a frontline regimen combining ponatinib and blinatumomab (starting in induction) with encouraging preliminary results. (141) Among the first 20 patients treated, CMRs were noted early in therapy, all patients achieved CR and the estimated 2-year survival was 93%. (116)

THE INTERMEDIATE LEUKEMIAS

Acute Lymphoblastic Leukemia in Older Patients (>60 Years Old)

Single-arm and randomized trials of inotuzumab and blinotumomab as single agents confirmed the high efficacy of both in refractory relapsed ALL: inotuzumab CR rate 74% versus 31% with standard of care; blinatumomab CR rate 44% versus 25% with standard of care. Modest but significant survival benefits were also observed, unlike the results in pediatric salvage ALL. (121–123,142, 143) In older ALL, intensive chemotherapy with Hyper-CVAD or other regimens produced reasonable CR rates ( 70% to 80%) but was associated with severe toxicities, an early mortality rate of 5% to 15%, a mortality rate of 20% to 30% in CR, poor tolerance of therapy, and ultimately with low 3- to5-years survival rates of 20% or less. (91,82) To improve upon the results and the drugs treatment values, we investigated the combination of low intensity chemotherapy (“mini-Hyper-CVD”) with inotuzumab and blinatumomab in ALL salvage and in older frontline ALL. (144–147) Among 70 patients (median age 68 years; range 60–81 years) treated with frontline mini-Hyper-CVD-inotuzumab-blinatumomab, the CR rate was 98%, the flow-cytometry MRD negative rate was 96%, and the 3-year survival was 54%, better than historical results with Hyper-CVAD in this age group. (146,147)

Stelljes and German colleagues used a similar approach with a low intensity chemotherapy “prephase” (cyclophosphamide-vincristine-steroids), fractionated inotuzumab induction with two consolidations, then five chemotherapy consolidation courses, and, finally, one year of maintenance with 6-mercaptopurine-methotrexate. Among 31 evaluable newly diagnosed patients (median age 65 years; range 56–80 years), the CR/CRi (complete remission with incomplete recovery of platelets and/or absolute neutrophil count) rate was 100%, the MRD negativity rate was 78%, and the 1-year survival 87%. (148)

Acute Myeloid Leukemia in Younger Patients (<60 years old)

Since the discovery of the activity of cytarabine and anthracyclines in AML, this combination, known more colloquially as “3+7,” has remained as the accepted standard of care for five decades. (20,21,149–151) In younger patients with AML, it produced estimated 5-year survival rates of 20% to 50% depending on the patient and leukemia characteristics, and treatment location (de novo versus therapy-related or secondary disease; co-morbidities; academic or National Cancer Institute- [NCI] designated cancer center versus community practice). (149–155) While progress in AML was perceived as stagnant or, at best, slow, several discoveries improved outcome. These included: 1) The addition of high dose cytarabine as consolidation for 4 courses. 2) The establishment of daunorubicin 60mg/m²daily x 3 or idarubicin 12mg/m² daily x 3 as superior to daunorubicin 45mg/m2 daily x 3, and equivalent to and less toxic than daunorubicin 90 mg/m² daily x 3. 3) The demonstration of the benefit of GO in favorable and intermediate-risk AML when given at a lower dose during induction and/or consolidation. 4) The establishment of allogeneic SCT as a safe and effective strategy in first and later remissions. 4) The improvement of antibiotic, antifungal and other supportive care measures, which reduced myelosuppression-related mortality during induction and in remission. (151)

Over the years, evidence accumulated that there were perhaps better regimens than 3+7, including high dose cytarabine during induction, adenosine nucleoside analogs (fludarabine, cladribine) added to the cytarabine-anthracycline backbone, and GO added to therapy.

More important breakthroughs happened recently with the discovery of the efficacy of targeted therapies such as venetoclax (BCL2 inhibitor), FLT3 inhibitors and IDH inhibitors, and confirmation of the value of adding them to the standard of care chemotherapy. These data have been detailed in other reviews. (20, 21,150,151) Many of the new agents are FDA approved as single agent therapy in refractory relapsed AML. However, considering their cost (>$20,000/month of therapy), a better treatment value may be derived from combining them with standard chemotherapy.

At our institution, the fludarabine-high dose cytarabine-idarubicin regimen (FAI, FLAG-IDA) and its equivalent with cladribine replacing fludarabine (CLIA) are frontline standards of care, to which we add targeted therapies based on patients’ disease characteristics. For example, when venetoclax was added to FLAG-IDA or CLIA in 79 newly diagnosed, younger patients, the result was an overall response rate of 90+%, and an estimated 1-year survival of 78+%. (156,157)

The addition of FLT3 inhibitors to chemotherapy improved the results in patients with FLT3-mutated AML. In the phase 3 RATIFY randomized trial of 717 younger patients (<60 years) with newly diagnosed FLT3-mutated AML, the addition of the first-generation FLT3 inhibitor midostaurin to 3+7 improved survival: median survival 74.7 versus 25.6 months, p =0.009; estimated 5-year survival rate 50% versus 42%. Most of the benefit noted among patients undergoing allogeneic SCT in first CR. (158) Pratz and colleagues treated 79 patients with newly diagnosed AML (56% FLT3 mutated) with 3+7 and the second-generation FLT3 inhibitor gilteritinib 120 mg daily for 14 days. They reported a composite CR (CR + CRi) rate of 82%, and an estimated 2-year survival rate of 70% in the FLT3-mutated cohort.(159) Rollig and colleagues treated younger/fit patients with newly diagnosed AML (FLT3-ITD in 17%) with standard chemotherapy and the first-generation FLT3 inhibitor sorafenib ( n=134) or placebo ( n=133). The addition of sorafenib improved the 5-year event-free survival rate (41% versus 27%; HR 0.68, p=0.011), and the 5-year relapse-free survival rate (53% versus 36%; HR 0.64, p= 0.035). Survival was similar, but 88% of relapsing patients underwent allogeneic SCT. This suggests that sorafenib, and perhaps other FLT3 inhibitors might also be beneficial in FLT3 wild type disease. (160).

Stein and colleagues treated 151 patients with newly diagnosed IDH-mutated AML with a combination of 3+7 and the IDH1 inhibitor ivosidenib (60 patients with IDH1 mutation) or the IDH2 inhibitor enasidenib (91 patients with IDH2 mutation). The overall response rates were 74%−77%; the estimated 1-year survival was 76%−78%. (161)

Of note, several of the studies mentioned earlier (156,157,159,161) showed encouraging results based on single arm or single institutional data. Confirmatory studies are needed.

Future improvements include refining the benefit/risk of combined strategies that might incorporate chemotherapy with more than one targeted therapy (for example GO + venetoclax, GO + FLT3 or IDH inhibitors, venetoclax + FLT3/IDH inhibitors) in simultaneous or sequential approaches. Discovering and adding safe and effective antibodies targeting CD33, CD123, CD70, others (ADCs or BiTEs) to chemotherapy or to eradicate MRD would be of value. Menin inhibitors may also improve the outcome in MLL-AML, and perhaps in NPM1-mutated disease and other molecular subsets.

Allogeneic SCT should be emphasized in AML, as its role is expanding in first remission, and its results improving over time. Allogeneic SCT in 2021 is vastly safer and more effective that at its beginnings in the early 1980s. It can be implemented in much older patients (up to the age of 75+years). By utilizing matched unelated donors, haplotype donors (with the use of cyclophosphamide of Day 4 post the preparative regimen) and cord blood as the sources of stem cells, almost every patient can potentially be a candidate for SCT. The procedure is safer today with the improvements in the preparative regimens, antibiotics and antifungals, and better supportive care measures and graft-versus-host prophylaxis and therapy.

THE DIFFICULT LEUKEMIAS

Older AML and Higher-Risk MDS

Older patients with AML who are fit for intensive chemotherapy and have favorable-intermediate risk features can be treated successfully with the regimens outlined above. For example, in a phase 1 trial in Australia, Chua and colleagues treated a group of fit older patients (65+ years, or 60+ years with monosomal karyotype) with a combination of an attenuated schedule of intensive chemotherapy (idarubicin x 2 days, conventional-dose cytarabine x 5 days; 2+5) and venetoclax 50–600 mg x 14 days (Days −6 to Day 7 of chemotherapy). (162) Among 51 patients treated (median age 72 years; range 62–80 years), the CR rate was 41%, the overall response rate (CR + CRi) 72%, and the median survival 11.2 months. Significant differences were reported in de novo versus secondary AML. In the former, the CR rate was 68%, CR+CRi rate 97%, and median survival 31.3 months. In 23 patients with secondary AML (70% prior hypomethylating agent [HMA] therapy for MDS), the CR rate was 9%, CR+CRi rate 43%, and the median survival 6.1 months. (162)

Even though the “difficult leukemias” occupy a small physical portion of this review, they may still represent 60%−65%+ of AMLs since the median age of patients is 68–70 years. These include not only those 70 years and older, but also younger patients with poor performance status, co-morbidities, therapy-related or secondary AML (post MDS or MPN), and adverse leukemic features [complex karyotype; monosomies in chromosomes 5, 7,and 17; t(11q23); others; mutations involving TP53, ASXL1, RUNX1; and MECOM AML). These subtypes have done poorly with traditional intensive chemotherapy over the past 50 years; they need alternative strategies. (150,151)

Before 2000, many older patients (ages 65–70 or older) were offered supportive care, palliation or hospice. The median survival was 3 months or less, or 4–6 months with poorly tolerated intensive chemotherapy. Progress in this area was the result of three factors: the understanding of the role of epigenetics in cancer; (163,164) the observed benefits of HMAs in MDS and their superiority to intensive chemotherapy; (165,166) and the benefit observed with low-dose cytarabine versus supportive care/ hydroxyurea (CR rate 18% versus 1%, p=0.00001; survival odds ratio of 0.60, p=0.0009). (167) This led to single arm and later randomized trials of the HMAs azacitidine and decitabine, which confirmed their benefits and resulted in approval by the European Medicines Agency (EMA) of HMAs for the treatment of older/unfit AML. (168,169) But the benefit was limited (median survival <12 months; 2-year survival <20%; CR rate 10%−20%; overall response rates <40%). Because adenosine nucleoside analogs (clofarabine, cladribine), cytarabine and HMAs are active and tolerable in this population when delivered in attenuated schedules, sequential low intensity triplet regimens were investigated. Among 248 patients (median age 69 years) treated, the CR rate was 59%, the induction mortality was 2%, and the median survival was 12.5 months. In patients with normal karyotype AML, the median survival was 19.9 months and the 2-year survival rate 45%. (170–172).

The discovery of the efficacy of venetoclax in AML changed its therapeutic outlook significantly. As a single agent, venetoclax has modest activity in refractory relapsed AML (response rate 18%), although it appears to be more active in newly diagnosed AML, based on the venetoclax therapeutic window which showed it to reduce blasts by 50% or more in 28% of patients after only 1 week of single agent venetoclax therapy. (162) Based on pre-clinical studies, venetoclax was combined with HMAs and with low dose cytarabine in single arm and, later, in randomized trials. (173–176). These confirmed the value of these combinations in older/unfit AML. The VIALE-A phase 3 trial randomized 431 newly diagnosed patients (75+ years or unfit for intensive chemotherapy) in a 2:1 fashion to azacitidine + venetoclax or azacitidine + placebo. The addition of venetoclax improved survival (median survival 14.7 versus 9.6 months; p<0.001), and the rates of CR+CRi (66.4% versus 28.3%; p<0.001), and CR (29.7% versus 17.9%; p<0.001). (175)Better results were noted among patients with normal karyoptype and those with IDH-mutated AML. Similar results were reported with the VIALE-C phase 3 trial comparing low-dose cytarabine +/− venetoclax. The venetoclax arm showed improved survival (median survival 8.4 versus 4.1 months; p= 0.11 at the study stated primary survival endpoint analysis; p=0.04 with an additional 6 months of follow-up) and the rates of overall response (48% versus 13%; p<0.001) and CR (27% versus 7%; p<0.001).(176). The HMAs plus venetoclax combinations are associated with significant survival improvement in patient with normal karyotype and those with IDH-mutated AML. The survival benefit is limited in FLT3-ITD AML ( need for the addition of FLT3 inhibitor) and absent in TP53-mutated AML. (175,177)

A longer schedule of decitabine (20 mg/m2 daily x 10) with venetoclax (21–28 days depending on the Day 21 marrow blasts) was investigated. Among 70 older/unfit patients (median age 72 years) with de novo AML, the CR rate was 66%, the CR + CRi rate was 85%, and the median survival was 18.1 months. (177)

Even though a combination of HMAs or low dose cytarabine plus venetoclax is now considered a standard of care in older/unfit AML, the results are still modest, with a projected 3–5-year survival rate < 40%−50%. To further improve the results, we added venetoclax to the triplet nucleoside analogs regimen: cladribine-low dose cytarabine-venetoclax alternating with azacytidine-venetoclax. Among the first 55 patients treated (median age 68 years; range 57–84 years), the CR rate was 78%, the overall response rate (CR + CRi) 93%, the MRD-negative rate among responders 84%, and the 1-year survival rate 70%. (178) These results compare favorably with historical experiences at our institution.

Additional important research discoveries include: 1) the confirmation of the benefit or maintenance therapy in AML, exemplified by the experiences with oral azacitidine maintenance, (8) as well as with FLT3 inhibitors as AML maintenance; (179,180) and 2) the development or oral HMAs( 100% absorbable oral decitabine-cedazuridine) which would facilitate treatment delivery in both AML and MDS. (178,179). The development of menin inhibitors and CD47 antibodies may hopefully improve the outcomes in some of the worse AML subsets, MLL-AML and TP53-mutated AML. (180–181) In an update of the results of the menin inhibitor SNDX-5631, among 31 evaluable patients with refractory relapsed acute leukemia treated with oral SNDX-5631 113–339 mg twice daily, the overall response rate was 48%, including 13 responses among 24 patients( 54%) with refractory relapsed MLL-AML ( Syndax update April 2021).

The hematologic disorders AML and higher risk MDS (>10% blasts; adverse cytogenetic-molecular abnormalities) share multiple pathophysiologic features and have similar outcomes with traditional therapies. Recent research questioned the established cut-offs of 30% blast, and later of 20% blasts versus 10% blasts as hard evidence to manage AML and higher risk MDS differently. (182) This led to some common research across the two diseases. The HMAs are effective in both MDS and AML, and combinations of HMAs with shorter dose schedules of venetoclax are under investigation in MDS. Nucleoside analog-based regimens (clofarabine, cladribine, cytarabine), topotecan, and omacetaxine also are effective in both diseases. Oral decitabine (decitabine and cedazuridine), approved for the treatment of MDS and CMML, may be used in AML, to make therapy more convenient. The approval of the oral formulation of azacitidine (CC486) for maintenance therapy in AML has reinvigorated the interest in maintenance therapy in higher risk MDS, and many strategies evaluating the use of oral agents are being investigated in both settings. We hope that the ongoing research in each entity will help the other through continued cross-fertilization and borrowed ideas.

SUMMARY

In a 2014 ASCO 50th anniversary editorial, Freireich and colleagues summarized half a century of discoveries in leukemia. Cancer (and medical) knowledge is contemporary, transient and rapidly changing. Therefore, it is perhaps not surprising that so much progress has occurred in the past 7–8 years, or even in the past 3 years since our 2018 update. (1, 2) For example, the 2014 editorial touches only briefly on the research with single agent blinatumomab and inotuzumab; there is little reference to CART research or to the use of ponatinib with chemotherapy and antibodies. All of the nine FDA- approved drugs in AML got the nod since, and the 2014 editorial does not highlight any of the discoveries related to venetoclax and the FLT3 and IDH inhibitors. The role of maintenance therapy in AML was confirmed only in 2020. The CML discussion does not mention the potential functional and molecular cure of CML. The CLL summary mentions the development of ibrutinib in a single sentence, but nothing about its potential cure with finite durations of BTK inhibitors and venetoclax.

Indeed, the view through the prism of therapeutic research and discoveries across all leukemias is optimistic. These will hopefully become mostly curable in our professional lifetime, while still leaving a lot of room for further improvements in efficacy and toxicity profiles of various strategies.