Evidence-Based Oncology
January 2023
Volume 29
Issue 1
Pages: SP13-SP20

ASH 2022: Leukemia and Lymphoma

Coverage from the 64th Annual American Society of Hematology Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana.

In R/R CLL, Zanubrutinib Offers 35% Improved PFS Over Ibrutinib; Edge Is Greater for Higher-Risk Patients

Patients with 1 prior treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia had a 35% improvement in progression-free survival (PFS) when taking zanubrutinib instead of ibrutinib, as final results of a head-to-head trial show the second-generation Bruton tyrosine kinase (BTK) inhibitor pulling away from its first-generation rival.1,2

In April 2022, investigators in the phase 3 ALPINE trial (NCT03734016) reported a primary end point showing zanubrutinib topping ibrutinib in overall response rate (ORR).3 At a late-breaking session at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December, investigators presented findings that showed zanubrutinib achieving superiority in PFS over ibrutinib after a median follow-up of 29.6 months. These data were simultaneously reported in the New England Journal of Medicine (NEJM).2 Zanubrutinib is sold in other indications as Brukinsa by BeiGene, which supported the study.

This is the first time a BTK inhibitor has shown superiority over another in both PFS and ORR, according to the study’s lead author, Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute in Boston, Massachusetts. Brown called the results practice changing, as did ASH Secretary Cynthia Dunbar, MD, chief of the Translational Stem Cell Biology Branch of the National Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, Maryland. “Progression-free survival is pretty much our gold standard for efficacy, so our data suggest that zanubrutinib should really become the standard of care in this setting,” Brown said in a statement.4

Besides the large overall PFS benefit seen at nearly 2.5 years, (HR, 0.65; 95% CI, 0.49-0.86; P = .002), investigators reported a 48% improvement in PFS at 24 months for zanubrutinib among high-risk patients with a 17p deletion, a TP53 mutation, or both (HR, 0.53; 95% CI, 0.31-0.88). Investigators in NEJM wrote that PFS benefits across other major subgroups “consistently favored zanubrutinib.”2

The large overall PFS benefit assessed by investigators at 29.6 months was similar to results assessed by an independent review committee; at 24 months, investigators found PFS rates were 78.4% and 65.9%, favoring zanubrutinib, according to data Brown presented at a news briefing.
The National Comprehensive Cancer Network has listed zanubrutinib as a preferred agent over ibrutinib in CLL in its guidelines, based on zanubrutinib’s improved safety profile. Brown noted this when asked whether there is still a role for ibrutinib in CLL.5 “I am not aware of a patient population in which I would select ibrutinib as compared [with] zanubrutinib,” Brown said.

Improved Mechanism
Ibrutinib (Imbruvica, Janssen) revolutionized CLL care after the FDA granted approval for relapsed or refractory patients in February 2014.6 It was more effective and had fewer adverse effects than chemotherapy, but off-target effects, especially those involving the heart, were a concern.

Zanubrutinib’s edge over ibrutinib is 2-fold. As Brown explained, the second-generation therapy is designed to have “greater BTK specificity than ibrutinib,” and its higher concentration offers more “sustained and complete” BTK inhibition and better efficacy. This improved mechanism reduces the cardiac effects associated with ibrutinib.

When asked about a separate trial (NCT02477696) involving the BTK inhibitor acalabrutinib (Calquence, AstraZeneca) vs ibrutinib in CLL,7 Brown said that trial involved high-risk patients only and was designed to show noninferiority, not superiority.

During the late-breaking session, Brown was asked how the results for the ibrutinib arm compared with historical expectations. She offered several examples from clinical trials as well as real-world evidence to show that the ALPINE results were consistent with prior findings. “I think what we see with ibrutinib is what’s actually achievable for patients in clinical practice,” she said.

ALPINE enrolled 652 patients from 15 countries who were randomly assigned to receive zanubrutinib (n = 327) or ibrutinib (n = 325). The 2 arms were balanced for demographic and disease characteristics: the median age was 67 years for the zanubrutinib group vs 68 years for the ibrutinib group, and the median prior lines of therapy was 1 for both groups. Notably, patients previously treated with a BTK inhibitor were excluded.

BeiGene reported the primary ORR end point at 24 months; final data reported at median follow-up of 29.6 months show ORR for zanubrutinib at 86.2% vs ibrutinib at 75.7%.3 The key secondary end point of PFS for zanubrutinib was assessed first for noninferiority and then for superiority; PFS was 35.0 months for the ibrutinib group and not reached for the zanubrutinib group.

Treatment discontinuation was lower for the zanubrutinib group (26.3%) compared with ibrutinib (41.2%), with most discontinuations due to adverse events (AEs), 16.2% vs 22.8%, respectively, or progressive disease, 7.3% vs 12.9%, respectively. Rates of AEs grade 3 or higher were 67.3% vs 70.4%, and serious AEs were 42.0% vs 50.0%. Dose interruption was 50.0% vs 56.8%, with dose reduction at 12.3% vs 17.0%, all favoring zanubrutinib. In sum, 48 patients (14.7%) treated with zanubrutinib died, compared with 60 (18.5%) treated with ibrutinib, with overall survival favoring zanubrutinib (HR, 0.76; 95% CI, 0.51-1.11), but not reaching statistical significance.

Cardiac Effects
In the other key secondary end point, rates of atrial fibrillation/flutter were 5.2% (n = 17) vs 13.3% (n = 43), favoring zanubrutinib. Discontinuation rates due to cardiac effects were 0.3% for zanubrutinib vs 4.3% for ibrutinib. There were no deaths due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib.

FDA Approval Pending
The findings are expected to be the last piece that FDA will need before acting on BeiGene’s supplemental new drug application (sNDA) for zanubrutinib’s use in CLL, which was filed in February 2022.8 CLL, which is diagnosed in approximately 21,000 patients a year in the United States and affects mostly older patients, accounts for about one-fourth of all new leukemia cases.9

Zanubrutinib is approved in the United States to treat 3 smaller populations: certain patients with mantle cell lymphoma, certain patients with marginal zone lymphoma, and those with Waldenström macroglobulinemia. Data from the American Cancer Society show that the combined number of new cases in these 3 cancers in the United States each year is approximately half the number of new US cases of CLL.9

Because ALPINE excluded patients previously treated with a BTK inhibitor, a reporter from The American Journal of Managed Care® asked during the news briefing if a future FDA label might include patients treated with a BTK inhibitor, including ibrutinib. Brown explained that the 2 drugs compared in the trial are both covalent inhibitors; in general, she said, if a patient developed disease progression on a covalent inhibitor, a second one would not be prescribed.

“However, if a [patient] was on ibrutinib for a while and stopped for an adverse event, or is having an adverse event on ibrutinib, then that [patient] could be switched to zanubrutinib with potentially significant benefit,” she said.

Brown noted that the sNDA is based on results from both ALPINE and SEQUOIA (NCT03336333), which examined zanubrutinib’s use in frontline treatment.10 “It’s likely to be a pretty broad label,” she said. 

Editors Note: FDA granted broad approval to zanubrutinib in CLL/SLL on January 19, 2023.


1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA-6.
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. Published online December 13, 2022. doi:10.1056/NEJMoa2211582
3. Bonavitacola J. Final response analysis of ALPINE finds zanubrutinib superior to ibrutinib in R/R CLL. The American Journal of Managed Care®. April 14, 2022. Accessed December 13, 2022.
4. Next-generation targeted therapy zanubrutinib found superior to ibrutinib for CLL and SLL. News release. American Society of Hematology. December 13, 2022. Accessed December 13, 20222.
5. Caffrey M. NCCN update moves zanubrutinib ahead of ibrutinib in CLL/SLL based on toxicity profile. Am J Manag Care. 2022;28(SP7):SP427.
6. deClaro RA, McGinn KM, Verdun N, et al. FDA approval for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590. doi:10.1158/1078-0432.CCR-14-2225
7. Wolska-Washer A, Robak T. Acalabrutinib: a Bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2022;15(3):183-194. doi:10.1080/17474086.2022.2054800
8. Joszt L. FDA accepts sNDA for zanubrutinib to treat CLL/SLL. American Journal of Managed Care®. February 23, 2022. Accessed December 13, 2022.
9. Key statistics about chronic lymphocytic leukemia. American Cancer Society website. Updated January 15, 2022. Accessed December 13, 2022.
10. Caffrey M. SEQUOIA: at 26 months, zanubrutinib prolongs PFS 58% over bendamustine + rituximab in patients with treatment-naïve CLL/SLL. The American Journal of Managed Care®. December 12, 2021. December 13, 2022.

Abstracts Highlight the Efficacy of BCL-2 Inhibitors in AML and CLL

The gene encoding B-cell lymphoma-2 (BCL-2) is highly expressed in many hematological malignancies, making it a promising target. Two abstracts presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition reviewed venetoclax, the first FDA-approved BCL-2 inhibitor in acute myeloid leukemia (AML) and a novel BCL-2 inhibitor to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Adding venetoclax to cladribine (CLAD) and low-dose ARA-C (LDAC) and alternating with azacitidine provides a highly effective, low-intensity regimen for older patients or patients unfit for intensive chemotherapy with newly diagnosed AML.1 Researchers from The University of Texas MD Anderson Cancer Center reported on results of a phase 2 study investigating the combination alternated with azacytidine, with composite complete response (CRc) rate as the primary end point. Overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity were the secondary end points.

The median age of the 93 patients included in the study was 68 years, with 28 patients 70 years or older and 1 patient who was younger than 60 years but considered unfit for intensive chemotherapy. The CRc rate was 92%, with 78% of patients having a CR and 14% of patients having CR with incomplete count recovery as best response. Furthermore, 5% of patients had no response and 2% of patients died.

A majority (84%) of patients achieved minimal residual disease (MRD) negativity during the study. Of patients with TP53-mutated disease, the CRc rate was 88% (86% achieving MRD negativity) and of patients with NPM1-mutated disease, the CRc rate was 96% (100% MRD negative). In addition, 41% of responders went on to receive allogeneic stem cell transplantation.

With a median follow-up of 22.8 months, the median duration of response, median DFS, and median OS were not reached. The estimated 24-month duration of response was 81.0% (95% CI; 71.0%-92.4%), DFS was 63.4% (95% CI; 52.1%-77.1%), and OS was 68.3% (95% CI; 58.1%-80.1%).

The researchers concluded that this regimen was well tolerated among older patients, but additional study of the regimen in older patients is needed.

Authors of a second abstract reviewed preliminary data of a phase 1 study of a novel inhibitor, BGB-11417, either alone or in combination with zanubrutinib in patients with CLL/SLL.2 Although venetoclax also is approved for CLL/SLL, BCL-2 mutations can result in resistance to the therapy, the authors explained.

The study included 2 cohorts: 6 patients who received monotherapy and 44 patients who received the combination with zanubrutinib. In the cohorts, patients received escalating doses (40 mg, 80 mg, 160 mg, 320 mg, or 640 mg once a day) of BGB-11417. In the monotherapy cohort, patients only received up to 160 mg daily, whereas patients in the combination cohort received up to 640 mg daily. Patients with treatment-naïve CLL only received up to 320 mg daily. In the combination cohort, patients also received either zanubrutinib 320 mg once a day or 160 mg twice daily. The zanubrutinib dose was initiated 8 to 12 weeks prior to starting BGB-11417.

The median follow-up was 11.5 months for monotherapy and 5.8 months for the combination. The maximum tolerated dose had not yet been reached for any CLL cohort.

The early results indicated the improved potency of BGB-11417 vs venetoclax, the researchers noted. Most patients had reductions in absolute lymphocyte count (ALC), and responses were seen at doses as low as 1 mg. In the monotherapy cohort, 66% of patients had a partial response or better. In the combination cohort, 72.7% of patients had a partial response with lymphocytosis or better.

The most common treatment-emergent adverse events in the monotherapy cohort were cytopenias. The most common in the combination cohort were contusion, neutropenia, and low-grade gastrointestinal toxicity. No patients discontinued monotherapy and only 1 patient discontinued combination therapy.

“Mature MRD data are forthcoming, and venetoclax-treated CLL/SLL cohorts will soon be open for enrollment,” the authors noted. 

1. Reville PK, Kantarjian H, Borthakur G, et al. Venetoclax added to cladribine (CLAD) + low dose AraC (LDAC) alternating with azacytidine (AZA) is highly active as frontline therapy in older patients with newly diagnosed acute myeloid leukemia in a phase 2 study. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 4074.
2. Cheah CY, Tam CS, Lasica M, et al. A phase 1 study with the novel B-cell lymphoma 2 (Bcl-2) inhibitor Bgb-11417 as monotherapy or in combination with zanubrutinib (ZANU) in patients (Pts) with CLL/SLL: preliminary data. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 962.

SPOTLIGHT: Patrick Reville, MD, MPH, Covers Study Results on Venetoclax Combined With CLIA

Patrick Reville, MD, MPH, instructor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses with Evidence-Based Oncology™ (EBO) the goals and findings of his study on venetoclax combined with cladribine, idarubicin, and cytarabine (CLIA) as an induction therapy for newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

EBO: What were the goals and main findings of your study?

Reville: The goal is really to try to improve upon the standard treatment that we give to patients with either newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Historically, we’ve separated the patients that are able to receive intensive chemotherapy or those that are not. For the patients that can receive intensive chemotherapy, the standard had been originally called 7+3, which is 2 chemotherapy drugs given intensively over about a week and then followed by a consolidation, which for patients that are eligible would be allogeneic stem cell transplant.
What MD Anderson has done over the last 10 or 15 years has been work to improve upon the chemotherapy portion of that. That’s kind of how the CLIA backbone was designed. It added a second purine analogue—the cladribine—and increase the dose of the cytarabine to a higher-dose cytarabine. That was the CLIA regimen. That work had been led by [Tapan M. Kadia, MD] within the group and it showed nice outcomes.

Still, we weren’t curing as many of these younger patients with AML as we had hoped. We hypothesized that we could add venetoclax to that combination. Venetoclax is a targeted drug targeting BCL-2. It’s been shown to be very active in AML, especially in patients that are ineligible for intensive chemotherapy. We added it to the intensive chemotherapy backbone and are showing good results.

I think that’s similar to what we had expected based on our experience in the lower-intensity therapy. Venetoclax does seem to be improving the outcomes for these patients. We, again, show that it’s very active. The response rate on this study was about 96%, which is higher than we would have expected with the CLIA alone or the standard 7+3 regimen alone. The longer-term outcomes seem to be showing encouraging efficacy. Patients are remaining in response longer and their survival seems to be improved with the addition of this regimen.

EBO: Did treatment results vary among patient groups?

Reville: The results, I’d say, in general, are pretty comparable among those 3 groups. We’ve enrolled 67 patients to date; 60 of those 67 had AML, 4 patients had high-risk MDS, and 3 patients had a mixed phenotype acute leukemia. The composite complete response (CRc) rate was 100% for the MDS and the mixed phenotype acute leukemia patients (MPAL), but those numbers are relatively small overall. I’d say that our interpretation of that data is that this regimen is similarly active in each of those 3 categories.

SPOTLIGHT: Ryan Jacobs, MD, Discusses Use of RWD to Compare Ibrutinib vs Acalabrutinib in First-line Treatment of CLL

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib revolutionized care for patients with chronic lymphocytic leukemia (CLL)/small cell leukemia when it was approved in 2014 for patients who had received at least 1 prior treatment. In 2016, use of ibrutinib expanded to patients for first-line treatment and “has been the treatment of choice,” according to investigators of studies presented at the 64th American Society of Hematology Annual Meeting and Exposition. One study used real-world data (RWD) to compare the time to next treatment between ibrutinib with second-generation BTK inhibitor acalabrutinib.1 A second study evaluated what happened when patients switched from first-line ibrutinib to acalabrutinib and found that 40% of patients who switched to acalabrutinib were likely to discontinue therapy.2 Both studies were led by Ryan Jacobs, MD, a CLL specialist and director of lymphoma at Levine Cancer Institute in Charlotte, North Carolina. While in New Orleans, Jacobs spoke with Evidence-Based Oncology™ (EBO) about the findings.

EBO: What led to the study examining time to next treatment?

Jacobs: CLL patients have benefited for many years now from the development of covalent BTK inhibitors. Ibrutinib was the first-in-class BTK inhibitor approved and it’s been available since 2014. More recently, we’ve had what we call second-generation BTK inhibitors come along; the only other FDA-approved option for CLL treatment in the United States is acalabrutinib, and it was approved in 2019. The approval of acalabrutinib was met with excitement because it had a more specific mechanism of action with less off-target kinase inhibition. The hope was that we would maintain the excellent efficacy that we had seen in the studies with ibrutinib, showing efficacy in both the first-line and the relapsed/refractory setting for CLL, but perhaps mitigating some of the toxicities that have occurred with use of ibrutinib. And so there is an interest in comparing these 2 options.

Obviously, the gold standard for comparing 2 drugs is a prospective clinical trial. And this has been done with ibrutinib vs acalabrutinib in the relapsed setting. That was the ELEVATE-RR study and that showed that the efficacy was mirrored between the 2 drugs—exactly the same PFS [progression-free survival] in these 2 groups in the relapsed setting.3 But the toxicity profile did have some differences. In particular, there was increased incidence of [atrial fibrillation]; that was in the ibrutinib arm, which was a secondary end point of that trial. So that is the data we have—other than that, we are left with cross-trial comparisons when trying to extrapolate into the first-line setting. Actually, the most popular, most used treatments because of their tolerability and efficacy are BTK inhibitors in the frontline setting.

So there is interest in how these 2 drugs compare to each other in the first-line setting. Unfortunately, it’s almost a bad element of how successful these drugs are [but] it would take a trial so long to compare these 2 options in the frontline setting that it’s unlikely we are going to get a prospectively done study comparing ibrutinib to acalabrutinib as a first-line treatment for CLL. As such, we looked for other areas to compare these options. Of course, we would be interested in the real-world outcomes when these agents are used first line because [we lack] any prospective head-to-head data. So we thought looking at a large group of patients that receive these 2 treatments as a first-line therapy and looking at a specific end point called time to next treatment would be a valid way to compare the 2, and it would be a clinically meaningful end point to look at.1

Typically, in a prospective study, PFS is observed. That’s difficult to show in looking in real-world data. In particular, with indolent lymphomas like CLL, you can have progression of disease but it doesn’t necessarily immediately lead to a next line of therapy. Some, including some oncologists and many patients, would argue time to next treatment might be a more meaningful end point than progression-free survival. Unfortunately, prospective studies don’t often extend their follow-up to look for time to next treatment, as that involves considerably more investment of both time and money to find an end point. So, this is a unique area that we can look at and leverage our real-world data. We used software from [Komodo Healthcare Map], an electronic medical record [EMR] analysis tool that looks not only at the patient but also at the patient medical records. It’s unique to maybe more well-known EMR analysis tools like Flatiron because it also uses pharmacy fill data, prescription information, which is a good way to look for time to next treatment, particularly when you’re evaluating between 2 oral therapies. So we can look at when the prescriptions were being refilled, when they were stopped, and when a patient went on to a new treatment.

EBO: What were the most important findings? Was there anything that surprised you?

Jacobs: We were a bit limited in our length of follow-up because we had to start in April of 2019. That was our landmark because that was when acalabrutinib was approved. It wouldn’t have necessarily been fair to look at these patients before acalabrutinib was widely available. So it’s only 2022 and BTK inhibitors are so effective. And in the end, going up to April of 2022, it is not, in the grand scheme of things, a very long follow-up period for BTK inhibitor-treated patients, but that’s what we had to work with.

So we started in 2019 at the date of approval; we wanted to try to select for first-line treatment patients. Now, that can be difficult to do in a real-world patient population using a big EMR data analysis. But with some precedent in other studies, we used a 12-month washout period. So patients had to have not had any other prescriptions for their CLL for 12 months before that 2019 landmark where we started the analysis. And that’s how we identified first-line–treated patients.

When we applied those rules and looked at the large patient database, we ended up with just over 700 ibrutinib patients treatment and around 373 acalabrutinib patients that were then able to be followed and observed for whether they started the next line of treatment. We were able to look at time periods over the next 12 months and 15 months; there is follow-up on these patients. And there was a statistically significant difference in time to next treatment, which was somewhat a surprise; I would say that ibrutinib actually had a longer time to next treatment. When we were looking at these 2 groups, about 7.5% acalabrutinib of patients had gone on to a next line of therapy vs only 5.9% of ibrutinib patients. To be sure, the absolute difference there is not large, but this is short follow-up.

When you look at the hazard ratio, that represents an 89% reduction in the likelihood of moving on to the next line of treatment, when comparing ibrutinib to acalabrutinib, in favor of ibrutinib. So, I would say that was a surprising finding. The prospective data had shown that acalabrutinib has better tolerability in terms of reduced discontinuation rates due to toxicity from the ELEVATE-RR study. So, to see that 2 drugs that have been shown to be similar in efficacy and 1 to have a favorable toxicity profile, but have actually the time to next treatment be better with the ibrutinib arm, I would say, is surprising.

1. Jacobs R, Lu X, Emond B, et al. Real-world comparison of time to next treatment for patients with CLL initiated on first-line treatment with ibrutinib vs acalabrutinib. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA: Abstract 797.
2. Jacobs R, Wang R, He J, et al. Real-world treatment patterns in patients with chronic lymphocytic leukemia and small cell leukemia switching form first line ibrutinib to acalabrutinib. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA: Abstract 3578.
3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

Impact of Patient Factors on Developing AML After MDS or CML; Ponatinib in Highly Resistant CP-CML

Certain patient and demographic characteristics that may be related to socioeconomic disparities impact the risk of developing acute myeloid leukemia (AML) after myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), according to research presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. The meeting was held December 10-13, 2022, in New Orleans, Louisiana.

While most cases of AML appear de novo in a patient who was previously healthy, it can progress from other conditions, such as MDS or myeloproliferative disorders. Researchers from the John H. Stroger, Jr Hospital of Cook County in Chicago, Illinois, and the University of Illinois College of Medicine at Chicago analyzed the Healthcare Cost and Utilization Project National Inpatient Sample and International Classification of Disease, Tenth Revision codes to identify adult patients admitted to a hospital between 2016 and 2019 who also had a secondary diagnosis of MDS or CML.1

Of the 79,579 patients hospitalized with AML, 4650 (5.8%) had a secondary diagnosis of MDS and 255 (0.3%) had a secondary diagnosis of CML. Both patients with MDS and CML were older than patients without those diagnoses: 69.9 years with MDS vs 61.4 years without and 62.8 years with CML vs 61.9 years without.

Among patients with AML who previously had MDS, a significantly higher proportion were male, White, had Medicare insurance, and were being treated at rural and urban non-teaching hospitals. In addition, a higher proportion were treated at small and medium-sized hospitals.

In the AML cohort, there was no difference between those who previously had MDS and those who did not in comorbidity burden, hospitalization region, and median household income.

Patients with a previous MDS diagnosis had higher odds of mortality compared with patients who did not previously have MDS, although the difference was not significant (13.0% vs 11.8%; adjusted odds ratio [AOR] 0.91, P = .41). Female patients had lower odds of mortality, although this was also not significantly different. Patients with MDS previously had a lower mean length of stay (15.3 days vs 18.5 days) and lower total hospital charges ($214,329 vs $254,635).

Among the patients who previously had CML, a higher proportion were female, Black and Hispanic, on Medicaid insurance, had lower household income, were treated in hospitals in the South region, and were treated at medium-sized hospitals compared with patients who had no previous CML diagnosis. However, these differences were not significant. There was also no difference between the 2 groups in comorbidity burden.

While patients who had a previous CML diagnosis had higher odds of mortality (17.5% vs 11.8%; AOR 1.6, P = .24), the difference was not statistically significant. Patients who were Black had significantly higher odds of mortality while female patients had non-significantly higher odds of mortality.

Similar to the group who previously had MDS, patients who had a previous diagnosis of CML had a lower mean length of stay (15.9 days vs 18.0 days) and lower total hospital charges ($231,116 vs $254,711).

Impact of Diabetes on CML Treatment
Another condition that can affect CML is diabetes. Results of a real-world study presented at ASH found that diabetes can affect both the clinical presentation of CML and the frontline treatment choice of patients with a new diagnosis.2

Most trials of tyrosine kinase inhibitors (TKIs) did not provide many opportunities for patients with multiple comorbidities to participate, requiring data from large cohorts in real-world practice to understand the management of newly diagnosed CML, researchers from across Italy explained.

They studied 1732 patients with chronic phase CML (CP-CML) diagnosed between 2012 and 2019 at 33 sites in Italy to understand the choice of TKI and incidence of early events during the first year of treatment. Patients were treated with frontline imatinib, dasatinib, or nilotinib. Imatinib is a first-generation TKI, while dasatinib and nilotinib are both second-generation TKIs.

Overall, 197 (11.4%) patients had concomitant diabetes. At baseline, patients with diabetes had a lower number of white blood cells compared with patients without diabetes. Compared with patients without diabetes, those with diabetes were older; had higher Sokal and EUTOS long-term survival scores, both of which predict survival; and were more likely to have other comorbidities, such as chronic obstructive pulmonary disease, arterial hypertension, previous neoplasm, ischemic heart disease, and cerebrovascular events.

A larger proportion of patients with diabetes were prescribed imatinib (72% vs 54%) or dasatinib (23.4% vs 15.3%), while a much higher proportion of patients without diabetes were prescribed nilotinib (30.7% vs 4.6%) (all P < .001). In the first year of treatment, 25.9% of patients with diabetes vs 18.7% of patients without had an early event that led to them permanently discontinuing frontline TKI treatment.

3-Year OPTIC Update
A 3-year update of the outcomes of the OPTIC trial (NCT02467270) highlighted the long-term efficacy and manageable safety profile of ponatinib in patients with highly resistant CP-CML, according to an abstract presented at ASH.3 The phase 2 OPTIC trial is evaluating the safety and efficacy of ponatinib, a third-generation TKI, in patients whose disease is either resistant to 2 or more prior TKIs or who have the T315I mutation. The study uses a response-based dose-adjustment strategy to optimize efficacy and improve the safety of the treatment.

The study randomized 238 patients to receive 45 mg (n = 94), 30 mg (n = 95), or 15 mg (n = 94) of ponatinib once daily. Nearly all (98%) of patients had received 2 or more prior TKIs, while half (55%) had received 3 or more, and 99% had discontinued at least 1 prior therapy because of resistance. Less than half (40%) had at least 1 baseline mutation and 23% specifically had the T315I mutation.

In the line of therapy prior to starting ponatinib, 61% of patients had achieved a complete hematologic response or worse as their best response to therapy. By 36 months in OPTIC:

(1) 60% of patients on 45 mg, 40% on 30 mg, and 30% on 15 mg had reached ≤1% BCR-ABL1IS.
(2) 4% of patients with T315I mutations on 45 mg, 25% on 30 mg, and 16% on 15 mg had achieved ≤ 1% BCR-ABL1IS.
(3) Among patients without T315I mutations, 59% on 45 mg, 44% on 30 mg, and 46% on 15 mg achieved ≤ 1% BCR-ABL1IS.
(4) Among patients who lost response at any time in the 45-mg and 30-mg groups, 60% and 33%, respectively, were patients who had T315I mutations.
For patients who had achieved ≤ 1% BCR-ABL1IS and then lost response when their doses were reduced to 15 mg, 27% in the 45-mg cohort and 11% in the 30-mg cohort had doses re-escalated. After re-escalation, 75% in the 45-mg group and 67% in the 30-mg group regained ≤ 1% BCR-ABL1IS.

The most common grade 3 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), hypertension (9%), and anemia (8%).

Based on the findings, the authors concluded that starting ponatinib at 45 mg and reducing to 15 mg after attaining ≤ 1% BCR-ABL1IS offered the optimal benefit-risk ratio.

Optimal Third-line Treatment in CP-CML
Another abstract presented at ASH highlighted the finding that third-line ponatinib is the optimal treatment selection for patients with CP-CML who fail 2 prior TKI therapies.4 Researchers led by Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center, retrospectively analyzed the combined patient-level data of third-line TKI therapy from the PACE (NCT01207440) and OPTIC studies as well as patients who were being treated at MD Anderson. They compared outcomes of patients on second-generation TKIs as third-line TKI therapy with ponatinib as third-line TKI therapy.

A total of 354 patents who received third-line TKI therapy (63 patients from PACE, 87 patients from OPTIC, and 204 patients from MD Anderson) were included with a median follow-up of 46 months. This study excluded patients who had T315I mutations.

Slightly more than half (51%) received ponatinib as third-line TKI therapy while the remaining patients received second-generation TKI (19% on dasatinib, 18% on nilotinib, and 11% on bosutinib). Prior to third-line therapy, the majority (88%) received imatinib, followed by 44% who received dasatinib, 45% nilotinib, and 10% bosutinib.

Compared with patients on second-generation TKIs, patients receiving ponatinib as the third-line therapy had:

(1) higher rates of nonischemic cardiovascular comorbidity;
shorter total duration of prior TKI therapies; and
(2) higher levels of BCR-ABL1 on the international scale.
Multivariate Cox regression using pre-matched data identified older age at the onset of third-line therapy and higher BCR-ABL1 levels as adverse prognostic factors for survival, while ponatinib in the third line was associated with a favorable survival (P = .003; HR, 0.435; 95% CI 0.253-0.748).

The 4-year progression-free survival for patients on second-generation TKI was 58% compared with 75% for patients on ponatinib (P < .001). The gap between the rates narrowed after propensity score matching (78% on second-generation TKI vs 89% on ponatinib; P = .0099). Prior to matching, the 4-year overall survival (OS) rates were 57% for second-generation TKIs vs 80% for ponatinib. After matching, OS rates were 78% for second-generation TKIs and 87% for ponatinib.

“Third-line ponatinib therapy is [the] optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation,” the authors concluded. 

1. Obeidat K, Turk E, Deenadayalan V, Litvin R, Zia M, Rifkin SD. Demographic characteristics and outcomes in patients with AML and previous diagnosis of CML or MDS. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 4032.
2. Capodanno I, Tiribelli M, Miggiano MC, et al. Choice of tyrosine kinase inhibitor and early events during the first year of therapy in newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with concomitant diabetes: a “Campus CML” study. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 1706.
3. Cortes JE, Deininger MW, Lomaia E, et al. Three-year update from the OPTIC trial: a dose-optimization study of 3 starting doses of ponatinib. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 620.
4. Jabbour E, Sasaki K, Issa GC, et al. Outcome of third-line tyrosine kinase inhibitors in patients with chronic myeloid leukemia in chronic phase: a propensity score analysis. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 333.

SPOTLIGHT Elias Jabbour, MD: For Patients With CML-CP Without T3151 Mutation, “If You Get to Third Line, Go for Ponatinib”

According to an abstract presented at the 64th American Society of Hematology Annual Meeting and Exposition, third-line ponatinib therapy is the optimal treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) without T3151 mutation who did not respond to 2 prior tyrosine kinase inhibitors (TKI). Elias Jabbour, MD, professor of medicine in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, tells Evidence-Based Oncology™ (EBO) how the propensity score analysis used modeling to come to this finding.
This transcript has been lightly edited for clarity.

EBO: How did your propensity score analysis allow you to use modeling to compare patients receiving ponatinib for third-line treatment of chronic phase CML with those receiving a second-generation TKI?

Jabbour: The outcome of the CML patient has changed drastically and patients in frontline can do so well. However, with increase of prevalence, patients living longer and longer, we’ve seen resistance happening about 5% per year. In the second line, there are several options available and that is standard. In a third-line therapy, we do not know what is the best sequence. A physician can switch from 1 second-generation TKI to another, or they move to ponatinib or dasatinib. So this sequence is not known.

We know ponatinib is very effective in CML. In fact, it does suppress the mutations and in studies done it has shown great outcome. That being said, the drug was associated with vascular events as an [adverse] effect and therefore people were worried about that, and rightly so.

After that, there was a trial called OPTIC (NCT02467270) where the investigators adjusted the dose of ponatinib based on efficacy. It means if you respond, we can reduce the dose, and by doing so, we improve on safety. And the study has shown that by doing so, we preserve the efficacy while improving on a safety profile. Therefore, we aimed in the study to compare [with] the use of second-gen TKI [tyrosine kinase inhibitor] because it’s hard to get a randomized trial done and to see which strategy is better. This was the aim.

Of course, it’s a retrospective review. So we went back to our database at MD Anderson and we worked with Takeda to get the cases from the OPTIC and PACE trials (NCT01207440) where we need to compare between ponatinib and a second-gen TKI. Then we performed what is called propensity score matching. That means we match patients. We tried to [match patients] to each other as close as possible to be able to compare efficacy, because otherwise you’ll be biased. And people may say, well, this drug did better because the population in here are not as aggressive as other population. To minimize the bias, we did what’s called propensity score matching between 2 populations. We look for responses, how deep responses can go; we look for PFS [progression-free survival] and survival.

First of all, we look at the characteristics of about 350 patients. We excluded T3151 mutation because these are resistant to secondary TKI. When we compared these 2 groups of patients, we noticed that those who received ponatinib had more risk factor for cardiovascular events. And we know these TKIs can have a side effect, angina, stroke, and others.

Despite that, we’ve seen more patients with risk factor for vascular events on ponatinib group. And we’ve seen as well that those who received ponatinib did so because of more aggressive disease—they have more disease at the baseline compared to patients who received second-gen TKI....Then, in order to minimize the difference, we did the matching, and then we went from 350 to almost 296 patients in each cohort. Then, we minimized the differences when it comes to risk factors. But despite the best matching with it, those who are on ponatinib had the high disease burden still. We define it by more than 10% BCR:ABL1 transcript, or more than 1% compared to the population who received second-gen TKI.

Then we look at the responses. Those received ponatinib had deeper responses compared to patients who received second-gen TKI. And that has been shown already. It’s a confirmation of what was reported before in a meta-analysis. But what’s new in our study is, not only that patients do respond, but patients live longer. We did what they called the PFS and survival, and we’ve shown that patients who received ponatinib had a better survival. That means, for certain doctors, they will say, well, ponatinib is not the best drug. I’m going to use another, safer drug, correct? And if I don’t do well, I can go to ponatinib. Such a strategy can compromise survival.

Therefore, the message from our presentation was do not waste time. If you get to the third line, go for ponatinib because it’s linked to a better survival. And to confirm these findings, we did the multivariate analysis and in the multivariate analysis we showed that ponatinib was the only factor favorably associated with survival benefit, and that is the main message from the study.

Now then we said maybe there’s some group of patients who are intolerant. Let’s focus on a group with a disease, real disease. We define them among experts in CML as above 1% [polymerase chain reaction]. We did repeat the analysis for this group of patients, and in this analysis, we’ve shown that the difference is more substantial in favor of ponatinib. Better outcome, better responses, and better outcome. Therefore, in conclusion, our study is confirming that ponatinib is superior to second-gen TKI rotation in a third-line therapy with deeper responses, better PFS, better survival, and that is more substantiated in patients with a high tumor burden. Therefore, I think the message is so clear that ponatinib is the most optimal strategy to be considered in a third-line setting. 

Jabbour E, Sasaki K, Issa GC, et al. Outcome of third-line tyrosine kinase inhibitors in patients with chronic myeloid leukemia in chronic phase: a propensity score analysis. Presented at: 64th American Society of Hematology Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 333.

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