INSIGHTS INTO ACUTE MYELOID LEUKEMIA June 22, 2020

Southeast Region

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2 CONTENTS

Topic Study Objective Report Snapshot Participant Demographics Key Insights Advisor Key Takeaways ARS Data – AML: Baseline and First-Line Therapy ARS Data – AML: Relapsed/Refractory Therapy

3 STUDY OBJECTIVE

> To gain advisors’ perspectives on the management of newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML)

4 REPORT SNAPSHOT

> A moderated, virtual roundtable discussion focusing on treatment of AML was held on June 22, 2020 > Disease state and data presentations were developed in conjunction with Dr Naval Daver from MD Anderson Cancer Center > The group of advisors comprised 9 community oncologists > Insights on the following AML therapies were obtained: azacitidine, cytarabine and daunorubicin (ie, 7+3), decitabine, ivosidenib, enasidenib, gemtuzumab ozogamicin, gilteritinib, liposomal daunorubicin and cytarabine, midostaurin, sorafenib, venetoclax, and glasdegib > Data collection was accomplished through use of audience response system (ARS) questioning and in-depth moderated discussion

5 Participant Demographics PARTICIPANT DEMOGRAPHICS (1/2)

What percentage of your AML patients fall into the poor-risk category? (N = 9)

11% 0 22% 1%–10% 11% 11%–20% 21%–30% 11% 31%–40% 41%–50% 44% ≥51%

A majority of advisors (88%) reported that >20% of their patients are categorized as poor-risk.

7 PARTICIPANT DEMOGRAPHICS (2/2)

What percentage of your AML patients are What percentage of your AML patients are 75 years or older? (N = 9) under 75 years old, but have comorbidities that prevent use of intensive chemotherapy? (N = 9)

11% 0 11% 0 22% 23% 1%–10% 11% 11% 1%–10% 11%–20% 11%–20% 21%–30% 21%–30% 11% 22% 31%–40% 22% 31%–40% 34% 41%–50% 41%–50% ≥51% 22% ≥51%

Eighty-nine percent of advisors reported that >20% of their patients are 75 years or older. More than half of that advisors (55%) indicated >20% of their patients are <75 years with severe comorbidities that prevent use of intensive induction chemotherapy.

8 Key Insights TOPLINE TAKEAWAYS – AML

First-Line Therapy

All advisors reportedly risk-stratify their newly diagnosed AML patients and base their treatment decision on patient’s age, comorbidities, and genomic/mutational analysis. Advisors routinely test for molecular markers (NPM1, FLT3, CEBPA, TP53, IDH1, and IDH2), but some advisors experience a significant delay in obtaining results, potentially impacting therapy timing. Most advisors refer patients fit for intensive chemotherapy to academic centers, but treat unfit patients themselves; HMA + venetoclax is the preferred treatment for the latter population. Advisors are aware of the appropriate venetoclax dose ramp-up schedule and dose modifications when coadministering antifungals, but some do not prescribe concurrent antifungals. Advisors are split on the treatment of patients with targetable IDH1/2 mutations; half would prescribe HMA + venetoclax, while the others would choose to use regimens with targeted agents.

Relapsed Therapy

All advisors test for a targetable mutation in their relapsed patients. For patients with targetable mutations, advisors showed a strong preference to target mutations in the relapsed/refractory setting or use transplantation when possible for younger, fit patients, and find hospice or best supportive care the final option. Advisors are optimistic for future data on combination therapies with targeted agents in the relapsed setting.

10 FIRST-LINE THERAPY (1/4)

Topic Data and Insights Risk stratification All advisors risk-stratify their newly diagnosed AML patients and base their treatment decision on patient’s age, comorbidities, and genomic/mutational analysis • All advisors risk-stratify their new AML patients prior to beginning therapy • Genomic and mutational analysis is the most common factor by which advisors risk-stratify their newly diagnosed AML patients (89%), followed by age (56%), comorbidities (44%), then lastly on the presence of prior hematologic malignancies (33%) Molecular All advisors routinely test for molecular markers in their newly diagnosed AML patients; some advisors experience a markers and significant delay in obtaining results, potentially impacting therapy timing genomic testing • All advisors routinely test for all the following molecular markers: NPM1, FLT3, CEBPA, TP53, IDH1, and IDH2 • Most advisors (89%) indicated that they send samples out for molecular/genomic testing, while 1 advisor indicated that sample testing is performed at their local hospital • Only a minority of advisors (22%) get the results of their genomic/mutational testing within a week, 44% of advisors wait between 8 and 14 days, and 33% wait 15–21 days • A majority of the advisors (78%) sometimes start AML frontline therapy before getting the genomic/mutational test results, 11% said they always start the frontline therapy before getting the results, while another 11% said they never start therapy without getting the results – During discussion, 1 advisor explained they only start frontline therapy prior to getting genomic/mutational test results in younger patients, but not older patients Referral pattern Most advisors refer patients fit for intensive chemotherapy to academic centers, but treat unfit patients themselves; HMA + venetoclax is the preferred treatment for the latter population • Most advisors refer their younger/fit patients for chemotherapy to leukemia specialists/academic centers, while a few do intensive chemotherapy induction themselves • Older patients unfit for intensive therapy are generally treated with HMA in combination with venetoclax

11 FIRST-LINE THERAPY (2/4)

Topic Data and Insights Patient case Proposed use of venetoclax (± HMA or LDAC) increased in patients over 75 years of age and in patients with certain scenarios comorbidities. Over half of the advisors indicated they would use venetoclax-based therapy in patients with IDH1 mutations • For a 50-year-old PS 0 patient with intermediate-risk AML (CD33 positive and FLT3 negative), all advisors would choose standard 7+3 either alone (56%) or in combination with gemtuzumab ozogamicin (44%) – However, if the same patient had PS 2 with a history of cardiovascular disease (previous heart attack), the majority of advisors (89%) would choose venetoclax (± HMA or LDAC) induction; the remaining advisor would again choose standard 7+3 alone (11%) • For a 77-year-old PS 1 patient with intermediate-risk AML (CD33 positive and FLT3 negative), 89% of the advisors would choose venetoclax (± HMA or LDAC) induction, while the other 11% would choose gemtuzumab ozogamicin • For a 70-year-old PS 1 patient with therapy-related AML following treatment for mantle cell lymphoma (including autologous stem cell transplant [ASCT]), 56% of the advisors would choose liposomal daunorubicin and cytarabine, and 44% would choose venetoclax (± HMA or LDAC) induction • For a 70-year-old PS 2 patient with intermediate-risk AML and IDH1 mutation, 56% of advisors would choose venetoclax (± HMA or LDAC), 33% would choose ivosidenib with HMA induction, and 1 advisor would choose ivosidenib alone • 67% of advisors would use standard induction chemotherapy + midostaurin to treat FLT3-positive AML patients, regardless of other risk factors

12 FIRST-LINE THERAPY (3/4)

Topic Data and Insights Perception of All advisors have experience using venetoclax and foresee that their future use of venetoclax will further increase in venetoclax newly diagnosed AML patients • All advisors have used venetoclax in at least 1 patient, with the majority (77%) having used it in 1–7 patients – During discussion, most advisors stated that they feel comfortable prescribing HMA + venetoclax for all patients, even those who have targetable mutations. A minority of advisors prefer to use regimens that include a targeted inhibitor – Most advisors indicated that venetoclax is given as outpatient treatment, and a few advisors indicated that their in- house pharmacies have venetoclax available for patients to start immediately • All advisors anticipate an increase in their use of venetoclax in newly diagnosed AML

Venetoclax Advisors are aware of the appropriate venetoclax dose ramp-up schedule and dose modifications when dosing and coadministering antifungals, but some do not prescribe concurrent antifungals modifications • In polling, 44% of advisors stated that they follow the recommended daily dose ramp-up for venetoclax, and another 44% start with 400 mg/day, while 1 advisor follows a 5-week dose ramp-up – Despite some advisors reporting they start with the 400-mg/day schedule or 5-week dose ramp-up regimen, during discussion, all advisors indicated they start with the recommended daily dose ramp-up for venetoclax – All advisors reported they give venetoclax intermittently, usually no more than 2 weeks of continuous venetoclax even during induction, and follow a “2 weeks on–2 weeks off” cycle • Three-fourths of advisors (75%) coadminister prophylactic antifungals while treating AML patients with venetoclax, and all advisors would modify the dose of venetoclax on the basis of antifungal use • A few advisors recounted issues regarding infection complications with venetoclax. For these situations, advisors reduced the dose of venetoclax but did not stop giving venetoclax, unless the patient developed neutropenic sepsis

13 FIRST-LINE THERAPY (4/4)

Topic Data and Insights Perception of Not all advisors have experience using ivosidenib and enasidenib, but those who do spoke positively of the agents ivosidenib and • 22% of advisors have used ivosidenib and 78% have prescribed enasidenib in their patients enasidenib – During discussion, when asked about treatment preference for IDH1/2-mutated patients, some advisors would use targeting agents either alone for older, unfit patients, or in combination with HMA for younger patients. Of the other advisors who would choose to proceed with venetoclax + HMA induction, 1 advisor indicated they would save IDH1/2- targeting agents for subsequent lines of therapy – Advisors currently using enasidenib recounted positive experiences in their patients

14 FIRST-LINE THERAPY QUOTES

“I've had IDH1 mutation in a 90-year-old, so I treated her with single- “I don't see any place where HMA-Ven cannot be prescribed. Even in agent ivosidenib. But if it's a 70-year-old, I would probably do the patients who have specific targeted mutations, I don't think there’s a ivosidenib with HMA.” subgroup where HMA-Ven did not have a good outcome. Even those who are IDH1 or IDH2 mutated, you can always give that agent next.“ “I haven't really seen a whole lot of CRS [with venetoclax], but we've [For a newly diagnosed patient, do you wait for the workup to come seen a lot of infection complications still.” back, the FLT3, IDH1, and IDH2, before treating with frontline therapy?] “Yes, for a younger patient, we do wait for that. Older, no.” [Regarding an IDH2-mutated patient currently on enasidenib] “She's been on it for about a month, and she's had a dramatic improvement in “If the patient gets readmitted for infections, we'll have to do dose all of her counts.” reductions and have to hold if it's a neutropenic sepsis.”

“We have an in-house pharmacy. And they always have venetoclax “I use HMA + Ven across the board, except for, of course, the really there.” young patients, who I hope to put in complete remission or send for a transplant.”

“If I get the FLT3 [results] right away, within 5 to 6 days maximum, and “In our practice, we are not giving more than 2 weeks of Ven, even if they're FLT3 positive, then I would abandon HMA-Ven and use 7+3 during induction.” plus Rydapt.”

“In my experience, giving continuous venetoclax is a real challenge. I “I think if you have the mutation, you might as well use the targeted don't know who can accomplish it, so generally 2 weeks on, 2 weeks drug. If I had a very viable patient that was FLT3 positive but was not fit off.” for intensive chemotherapy, I would probably reach out and make sure there's toxicity data, and try to give them all 3 drugs.”

15 RELAPSED/REFRACTORY THERAPY (1/2)

Topic Data and Insights Biomarkers and All advisors repeat biomarker testing in their R/R AML patients mutations • A majority of advisors (89%) would do a full repeat biomarker profile in their AML patients at the time of relapse, while 1 advisor indicated they would only test for specific biomarkers • Most advisors (78%) indicated IDH1/2 and FLT3 as the most important biomarkers to be tested for in R/R AML, while 22% considered TP53, IDH1/2, and TET2 to be the most important • 44% of the advisors each require a CR1 of at least 6 months or 12 months before recommending reinduction in their relapsed AML patients, while 1 advisor indicated they require a CR1 of at least 18 months • 55% of the advisors reported that up to 20% of their R/R AML patients are FLT3 mutated, while 44% reported up to 30% FLT3-mutated R/R AML patients • IDH1/2 mutations were reported in up to 30% of advisors’ R/R AML patients • A majority of the advisors (88%) always check for FLT3 mutation in R/R AML patients, regardless of its status at baseline Patient case During discussion, advisors showed a strong preference to target mutations in the relapsed/refractory setting or use scenarios transplantation when possible for younger, fit patients, and find hospice or best supportive care the final option • Scenario: 58-year-old relapsed FLT3-ITD–mutated AML patient who received induction and 4 cycles of consolidation with 7+3 + midostaurin (but no ASCT or midostaurin maintenance); currently with 12K WBC, 9.2 Hgb, 42K platelets, PS 1, and no acute symptoms – 56% of advisors would start gilteritinib therapy immediately. Only 22% would start HMA + venetoclax, with another 11% of advisors each proceeding with FLAG-Ida followed by ASCT or rushing FLT3 mutation evaluation • Scenario: 52-year-old relapsed AML patient with inv(16), PS 0, and no major comorbidities (prior induction with standard 7+3 and 4 cycles of HiDAC consolidation) – More than half of the advisors (67%) would refer the patient to an academic center for bone marrow transplant (BMT) evaluation and a decision on reinduction; 1 advisor each indicated they would repeat 7+3 induction, treat with liposomal daunorubicin-cytarabine, or treat with HMA + venetoclax

16 RELAPSED/REFRACTORY THERAPY (2/2)

Topic Data and Insights Patient case • Scenario: Patient induced with liposomal daunorubicin and cytarabine, who shows 20% cells and 35% blasts on day 14 scenarios (cont) marrow – 67% of the advisors would continue liposomal daunorubicin and cytarabine on days 1 and 3. Others would either go with HMA + venetoclax (11%), CLAG-M (11%), or FLAG-Ida (11%) • Scenario: 77-year-old AML patient (normal cytogenetics, no FLT3-ITD/NPM1/CEBPA mutations, but IDH2 and DNMT3 mutations) with a positive day 14 marrow after 7+3 and several fungal infections during induction – 67% would prescribe enasidenib, 22% would start with HMA + venetoclax, and 11% would give ivosidenib • Scenario: 54-year-old relapsed AML patient with FLT3-ITD and DNMT3 mutations at relapse (and WBC 43K, Hgb 8.2, platelets 12), with history of a previous induction with 7+3 and midostaurin (leading to CR), 1 consolidation with HiDAC + midostaurin, and transplant (with no posttransplant maintenance and relapse in 9 months) – A majority of the advisors (89%) would prescribe single-agent gilteritinib followed by a second transplant and posttransplant maintenance with gilteritinib. One advisor would give azacitidine + venetoclax followed by second transplant and posttransplant maintenance • Scenario: 75-year-old high-risk myelodysplastic syndrome (MDS) patient (with a history of prostate cancer and treatment with radiotherapy 3 years ago) with pancytopenia, 11% blasts (cytogenetics revealing +8 and –7), and progressive disease (PD) on HMA therapy, currently with 25% blasts after a 9-month response – 44% of the advisors would choose to prescribe HMA + venetoclax, while 33% would choose LDAC + glasdegib, and the remaining 22% would prescribe liposomal daunorubicin-cytarabine

17 RELAPSED/REFRACTORY THERAPY QUOTES

“If there's a target, go for the target, and a clinical trial for a patient “Find something that is potentially targetable. If you can target it, go who's fit. If not, then I think comfort care measures probably is with a FLT3 or IDH1 or IDH2 mutation-specific TKI if it hasn't been appropriate.” used prior. And if you don't have anything that is potentially targetable, if they are fit, then you know your friendly transplanter to call. If they're not, then the outcomes are relatively poor with cytotoxic therapy. And in “In the relapsed group, you'd want to look for the target and see if they the right patient, hospice may be the right idea.” qualify for an inhibitor. Usually, I give a single agent. Younger, fit patient, you want to see if they could have a transplant option. And then unfortunately, a lot of my patients, if they don't have a mutation, then “Relapsed patients typically get FLAG-Ida at UAB. We used CLAG-M we would look at hospice or best supportive care.“ before. But we prefer to do FLAG-Ida.”

“Relapsed/refractory, if you're FLT3 positive, you're getting gilteritinib, because it beat chemotherapy for overall survival. And if you're FLT3 “If they have any targetable mutations, I would put them on the IDH1, negative, then it would depend on the situation. If you're IDH1 or IDH2 IDH2, or the FLT3 inhibitor.” mutated, then I have been using single agent. But I think it may be okay to start thinking about combination IDH1 and IDH2 with Aza. I still have Mylotarg on the radar for relapse if they haven't received it.” “If they have a targetable mutation, they get a single-agent inhibitor. But I think combination with doublets or triplets may be the future.” “I've only been using IDH1 and IDH2 for relapse, single-agent for relapse so far. So far, very good. All of my patients have had some benefit. None of them have been refractory to it.”

18 Advisor Key Takeaways ADVISOR KEY TAKEAWAYS (1/2)

Dr 1 Dr 2 • HMA + venetoclax is a really good combination for elderly patients • There is a learning curve to dose adjusting venetoclax especially who are transplant-ineligible • Use more antifungals with venetoclax • The need for a significant amount of venetoclax dose reduction with • Look for mutations and target the mutations the concomitant use of azoles • In the relapsed setting, Idhifa can be used Dr 3 Dr 4 • Ven/aza is applicable to most patients, especially those with elderly • Managing toxicity of IDH1 and IDH2 inhibitors and the future of AML combinations with these agents • Appropriate venetoclax dosing with azoles is critical for maintaining • Gilteritinib in pre- and post-transplant for relapsed FLT3-positive efficacy and lowering toxicity disease • Targeted therapy combinations of venetoclax with some of the TKIs • Use of gemtuzumab ozogamicin for first-line treatment and the overall is how we can move the field forward in R/R AML survival advantage for patients who were good risk Dr 5 • Don’t shy away from using antifungals with venetoclax, and dose adjust appropriately • Combinations of venetoclax in the relapsed/refractory setting • Availability of targeted TKI inhibitors

20 ADVISOR KEY TAKEAWAYS (2/2)

Dr 6 Dr 7 • Data of venetoclax + the targeted agents • Maintenance is important, whether it’s oral azacitidine or continuing • HMAs may not be that crucial for the mutated patients parenteral azacitidine • Use of oral azacitidine as maintenance • Importance dosing adjusting venetoclax, especially with antifungals • It’s still a debatable issue whether or not to test bone marrow in the older patients Dr 8 Dr 9 • Learning to properly dose adjust of venetoclax • Genetic testing is important • Intermittent vs continuous administration venetoclax after the first • Will start to incorporate new drugs cycle • Dosing and interactions of venetoclax • Importance of fungal prophylaxis

21 AML ARS BASELINE AND FIRST-LINE THERAPY DO YOU RISK-STRATIFY YOUR NEWLY DIAGNOSED AML PATIENTS? (N = 7*)

120

100 100

40 Percentage of physicians of Percentage

0 0 0 Yes, for all Yes, for some No, I don’t

23 *Two advisors did not respond. IF YOU RISK-STRATIFY YOUR NEWLY DIAGNOSED AML PATIENTS, WHAT METHOD DO YOU USE? SELECT ALL THAT APPLY (N = 9) 100 89 90

60 56

50 44 40 33

30 Percentage of physicians of Percentage 20

10 0 0 Clinical factors Age On the basis of presence Genomic and mutational I don't risk-stratify (comorbidities, etc) of prior hematologic analysis malignancies 24 24 IN ADDITION TO CYTOGENETICS, WHICH OF THE FOLLOWING MOLECULAR MARKERS ARE YOU ROUTINELY TESTING FOR IN YOUR NEWLY DIAGNOSED AML PATIENTS? (SELECT ALL THAT APPLY) (N = 9)

120

100 100

40 Percentage of physicians of Percentage

0 0 0 0 0 0 0 NPM1 mutation FLT3 mutation CEBPA mutation TP53 mutation IDH1 mutation IDH2 mutation All of the above (ITD or TKD)

25 WHEN IT COMES TO MOLECULAR/GENOMIC TESTING: (N = 9)

100 89 90

Percentage of physicians of Percentage 30

20 11 10 0 0 I send the sample out The sample is tested in my local hospital I do not test

26 26 WHEN IT COMES TO GENOMIC/MUTATIONAL TESTING, THE TURNAROUND TIME TO GET THE FINAL RESULTS IS: (N = 9)

45 44

35 33

25 22 20

Percentage of physicians of Percentage 15

5 0 0 <7 days 8–14 days 15–21 days ≥22 days

27 IN GENERAL, THE FOLLOWING STATEMENT DESCRIBES ME BEST: (N = 6*)

80 78

Percentage of physicians of Percentage 20 11 11 10 0 0 I never start AML frontline I sometimes start AML frontline I always start AML frontline I do not perform therapy before I have the therapy before I have the therapy before I have the mutational/genomic testing genomic/mutational test results genomic/mutational test results genomic/mutational test results available available available

28 *Three advisors did not respond. IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG LIPOSOMAL DAUNORUBICIN AND CYTARABINE (VYXEOS)? (N = 9) 50

45 44

35 33

Percentage of physicians of Percentage 15 11 11 10

5 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

29 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG GEMTUZUMAB OZOGAMICIN (MYLOTARG)? (N = 9)

45 44

25 22 20

Percentage of physicians of Percentage 15 11 11 11 10

5 0 0 0 1–3 4–7 8–10 11–15 ≥16

30 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG MIDOSTAURIN (RYDAPT)? (N = 9)

60 56

40 33

20 Percentage of physicians of Percentage

11 10

0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

31 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG GILTERITINIB (XOSPATA)? (N = 9)

60 56

50 44

20 Percentage of physicians of Percentage

0 0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

32 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG ENASIDENIB (IDHIFA)? (N = 9)

80 78

30 Percentage of physicians of Percentage 22 20

10 0 0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

33 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG IVOSIDENIB (TIBSOVO)? (N = 9)

80 78

30 Percentage of physicians of Percentage 22 20

10 0 0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

34 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG GLASDEGIB (DAURISMO)? (N = 9)

100 89 90

Percentage of physicians of Percentage 30

20 11 10 0 0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

35 IN HOW MANY UNIQUE AML PATIENTS HAVE YOU USED THE DRUG VENETOCLAX TABLETS (VENCLEXTA)? (N = 9)

45 44

35 33

25 22 20

Percentage of physicians of Percentage 15

5 0 0 0 0 0 1–3 4–7 8–10 11–15 ≥16

36 WHAT INDUCTION REGIMEN DO YOU ROUTINELY RECOMMEND FOR A 50-YEAR-OLD PS 0 PATIENT WITH INTERMEDIATE-RISK AML (CD33 POSITIVE AND WITHOUT FLT3 MUTATION)? (N = 9)

60 56

50 44

20 Percentage of physicians of Percentage

0 0 0 0 0 0 0 0 0 Standard 7+3 HiDAC plus Liposomal HMA LDAC (± HMA) Gemtuzumab Standard 7+3 Venetoclax (± LDAC plus Other anthracycline daunorubicin ozogamicin plus HMA or LDAC) glasdegib and cytarabine gemtuzumab ozogamicin

37 WHAT INDUCTION REGIMEN WOULD YOU RECOMMEND FOR A 50-YEAR- OLD PS 2 PATIENT WHO HAS A HISTORY OF CARDIOVASCULAR DISEASE, INCLUDING A PREVIOUS HEART ATTACK, WITH INTERMEDIATE-RISK AML (CD33 POSITIVE AND WITHOUT FLT3 MUTATION)? (N = 9) 100 89 90

30 Percentage of physicians of Percentage 20 11 10 0 0 0 0 0 0 0 0 0 Standard 7+3 HiDAC + Liposomal HMA LDAC (± HMA) Gemtuzumab Standard 7+3 Venetoclax (± LDAC + Other anthracycline daunorubicin ozogamicin plus HMA or LDAC) glasdegib and cytarabine gemtuzumab ozogamicin

38 WHAT INDUCTION REGIMEN DO YOU ROUTINELY RECOMMEND FOR A 77-YEAR-OLD PS 1 PATIENT WITH INTERMEDIATE-RISK AML (CD33 POSITIVE AND WITHOUT FLT3 MUTATION)? (N = 9)

100 89 90

30 Percentage of physicians of Percentage 20 11 10 0 0 0 0 0 0 0 0 0 Standard 7+3 HiDAC plus Liposomal HMA LDAC (± HMA) Gemtuzumab Standard 7+3 Venetoclax (± LDAC plus Other anthracycline daunorubicin ozogamicin plus HMA or LDAC) glasdegib and cytarabine gemtuzumab ozogamicin

39 WHAT INDUCTION REGIMEN DO YOU ROUTINELY RECOMMEND FOR A 70- YEAR-OLD PS 1 PATIENT WITH THERAPY-RELATED AML FOLLOWING TREATMENT FOR MANTLE CELL LYMPHOMA (INCLUDING AUTOLOGOUS STEM CELL TRANSPLANT)? GENOMIC PROFILING IS UNKNOWN. (N = 9) 60 56

50 44

20 Percentage of physicians of Percentage

40 WHAT INDUCTION REGIMEN DO YOU RECOMMEND FOR A 70- YEAR-OLD PS 2 PATIENT WITH INTERMEDIATE-RISK AML AND IDH1 MUTATION REVEALED BY NGS? (N = 9) 60 56

40 33 30

20 Percentage of physicians of Percentage 11 10

0 0 0 0 Venetoclax (± HMA LDAC + glasdegib Ivosidenib Ivosidenib + HMA Ivosidenib plus 7+3 Gemtuzumab or LDAC) ozogamicin + HMA

41 I AM CURRENTLY TREATING ALL FLT3 MUTATION-POSITIVE AML PATIENTS WITH STANDARD INDUCTION CHEMOTHERAPY PLUS MIDOSTAURIN, WHENEVER FEASIBLE, REGARDLESS OF OTHER RISK FACTORS. (N = 9) 80

70 67

40 33 30

Percentage of physicians of Percentage 20

10 0 0 Agree Disagree I have not treated a FLT3 mutation-positive AML patient since the approval of midostaurin

42 VENETOCLAX HAS BEEN APPROVED FOR NEWLY DIAGNOSED ADULT AML PATIENTS WHO ARE 75 YEARS OR OLDER, OR WHO HAVE COMORBIDITIES THAT PRECLUDE USE OF INTENSIVE INDUCTION CHEMOTHERAPY. DO YOU PLAN TO INCREASE YOUR USE OF THIS THERAPY OPTION IN NEWLY DIAGNOSED AML PATIENTS? (N = 9) 120

100 100

Percentage of physicians of Percentage 40

0 0 0 Yes No I am not sure yet

43 WHICH OF THE FOLLOWING DOSING SCHEDULES DO YOU USE FOR VENETOCLAX IN AML? (N = 9)

45 44 44

Percentage of physicians of Percentage 15 11 10

5 0 0 0 5-week dose ramp-up Daily dose ramp-up Start with 400 mg/day Start with 600 mg/day Other – please describe

44 DO YOU COMMONLY COADMINISTER PROPHYLACTIC ANTIFUNGALS WHEN TREATING AML PATIENTS WITH VENETOCLAX? (N = 8*) 80 75

25 Percentage of physicians of Percentage 20

0 Yes No

45 *One advisor did not respond. DO YOU MODIFY YOUR DOSING OF VENETOCLAX ON THE BASIS OF PROPHYLACTIC ANTIFUNGALS USE? (N = 8*)

120

100 100

40 Percentage of physicians of Percentage

0 0 Yes No

*One advisor did not respond. 46 AML ARS RELAPSED/REFRACTORY THERAPY DO YOU ROUTINELY REPEAT BIOMARKER TESTING IN YOUR AML PATIENTS AT THE TIME OF RELAPSE? (N = 9)

100 89 90

Percentage of physicians of Percentage 30

20 11 10 0 0 Yes, I do a full repeat biomarker profile Yes, but I only test for specific biomarkers No

48 WHICH OF THE FOLLOWING MUTATIONS ARE MOST IMPORTANT TO BE CHECKED IN ALL PATIENTS WITH RELAPSED AML FOR THERAPEUTIC DECISION MAKING? (N = 9)

80 78

30 Percentage of physicians of Percentage 22 20

10 0 0 0 0 TP53, IDH1/2, TET2 TET2, ASXL1, RUNX1 IDH1/2 and FLT3 FLT3, ASXL1, EZH2 DNMT3, ASXL1, TET2

49 I GENERALLY REQUIRE A CR1 OF AT LEAST __ MONTHS BEFORE RECOMMENDING REINDUCTION IN MY RELAPSED AML PATIENTS. (N = 9) 50

45 44 44

Percentage of physicians of Percentage 15 11 10

0 6 12 18

50 WHAT PERCENTAGE OF THE R/R AML PATIENTS YOU SEE ARE FLT3 MUTATED (ITD AND TKD INCLUDED)? (N = 9)

45 44

35 33

Percentage of physicians of Percentage 15 11 11 10

5 0 0 0 0 0 1%–10% 11%–20% 21%–30% 31%–40% 41%–50% ≥51%

51 WHAT PERCENTAGE OF THE R/R AML PATIENTS YOU SEE ARE IDH MUTATED (IDH1 AND IDH2 INCLUDED)? (N = 9)

45 44

35 33

25 22 20

Percentage of physicians of Percentage 15

5 0 0 0 0 0 0 1%–10% 11%–20% 21%–30% 31%–40% 41%–50% ≥51%

52 HOW OFTEN DO YOU RECHECK FLT3 MUTATIONS AT RELAPSE, IRRESPECTIVE OF BASELINE FLT3 MUTATION STATUS? (N = 8*) 100

90 88

Percentage of physicians of Percentage 30

20 12 10 0 0 0 Never <50% of the time >50% of the time Always

53 *One advisor did not respond. PATIENT CASE

> A 58-year-old with FLT3-ITD–mutated AML (allelic ratio 0.55) received induction and 4 consolidations with 7+3 + midostaurin. He did not want to undergo ASCT, and maintenance with midostaurin was not given. He relapsed 5 months after his last consolidation. His WBC is 12K, Hgb 9.2, platelets 42K, and he has PS 1, with no acute symptoms

54 54 WHAT WOULD BE THE NEXT BEST STEP IN MANAGEMENT? (N = 9)

60 56

22 20

Percentage of physicians of Percentage 11 11 10

0 0 Proceed with FLAG-Ida Start gilteritinib therapy Repeat FLT3 mutation Reinduce with 7+3 plus Give HMA + venetoclax followed by ASCT immediately evaluation and rush the midostaurin test

55 PATIENT CASE

> A 52-year-old female who has inversion 16 completes standard induction with 7+3, and 4 cycles of consolidation with HiDAC. One-and-a-half years following completion of consolidation, she relapses with AML, and inversion 16

56 56 WHAT DO YOU TREAT HER WITH, PROVIDED SHE HAS PS 0 AND NO MAJOR COMORBIDITIES? (N = 9)

I would refer to an academic center for BMT 67 evaluation and a decision on reinduction LDAC + glasdegib 0

HMA + venetoclax 11

Decitabine – 10 days 0

Decitabine – 5 days 0

Azacitidine 0

FLAG-idarubicin 0

CLAG-M 0

Liposomal daunorubicin-cytarabine 11

Repeat 7+3 11

0 10 20 30 40 50 60 70 80

Percentage of physicians 57 PATIENT CASE

> A patient who was initially treated with induction liposomal daunorubicin- cytarabine has a day 14 marrow that shows reduction in disease, but still 20% cellular with 35% blasts

58 58 WHAT WOULD YOU CONSIDER NEXT? (N = 9)

LDAC + glasdegib 0

HMA + venetoclax 11

Decitabine – 10 days 0

Decitabine – 5 days 0

Azacitidine 0

FLAG-idarubicin 11

CLAG-M 11

MEC 0

Liposomal daunorubicin-cytarabine days 1 and 3 67

Standard 7+3 0

0 10 20 30 40 50 60 70 80 Percentage of physicians 59 PATIENT CASE

> A 77-year-old male presents with AML, normal cytogenetics, no FLT3- ITD/NPM1/CEBPA mutation. He receives 7+3 and has a positive day 14 marrow. He develops a significant fungal infection during induction, and you do not want to give him reinduction. Next-generation sequencing shows IDH2 and DNMT3 mutations

60 60 WHAT DO YOU CONSIDER NEXT? (N = 9)

70 67

30 22 Percentage of physicians of Percentage 20 11 10 0 0 0 0 0 0 Azacitidine Enasidenib Ivosidenib Decitabine – 5 Decitabine – 10 Gemtuzumab HMA + LDAC + days days ozogamicin venetoclax glasdegib

61 PATIENT CASE

> A 54-year-old patient with AML, FLT3-ITD allele ratio 0.62, DNMT3a, EZH2, TET2 mutations receives induction with 7+3 + midostaurin and achieves CR. She receives 1 consolidation with HiDAC + midostaurin and goes to transplant. She does not receive posttransplant maintenance. She relapses 9 months posttransplant. Bone marrow at relapse shows FLT3-ITD 0.52, DNMT3, and no other mutations. Her WBC count is 43K, Hgb 8.2, platelets 12

62 62 WHAT WOULD YOU RECOMMEND? (N = 9)

100 89 90

Percentage of physicians of Percentage 20 11 10 0 0 0 0 0 Repeat 7+3 + Azacitidine + sorafenib Azacitidine + venetoclax Single-agent gilteritinib CLAG-M with midostaurin Palliative care midostaurin followed by 2 followed by a second followed by a second followed by a second followed by a transplant DLIs transplant if possible transplant and posttransplant and posttransplant maintenance transplant maintenance with gilteritinib

63 PATIENT CASE

> A 75-year-old man with high-risk MDS has history of prostate cancer treated with radiation therapy 3 years ago. During follow-up, he was found to have pancytopenia. BM evaluation revealed 11% blasts. CG revealed +8 and –7. Patient received HMA therapy and achieved a response for 9 months. Evaluation revealed 25% blasts with progressive disease

64 64 WHAT WOULD YOU CONSIDER NEXT? (N = 9)

Gemtuzumab ozogamicin 0

HMA + venetoclax 44

FLAG-idarubicin 0

LDAC + glasdegib 33

LDAC 0

Liposomal daunorubicin-cytarabine 22

Standard 7+3 0

0 5 10 15 20 25 30 35 40 45 50

Percentage of physicians