Oral Chemotherapy Clinical Pearls in AML

Oral Chemotherapy Clinical Pearls in AML

Rob Walchack, PharmD, BCOP

Hematology/Cellular Therapy Clinical Pharmacy Specialist

UK HealthCare

September 17, 2021

Disclosures

I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation.

Objectives

Identify relevant drug-drug interactions with oral chemotherapy agents in AML

Describe oral chemotherapy dose adjustments in AML

Abbreviations

FLT3-ITD = fms-related tyrosine kinase 3 gene-internal tandem duplication

FLT3-TKD = fms-related tyrosine kinase 3 gene-tyrosine kinase domain

IDH1, IDH2 = isocitrate dehydrogenase 1 and 2

BCL2 = B-cell lymphoma 2

IC = intensive chemotherapy

7+3 = cytarabine continuous infusion x 7 days + daunorubicin x 3 days

VEN = venetoclax

LDAC = low-dose cytarabine

HMA = hypomethylating agent

DEC = decitabine

AZA = azacitidine

FluMel = fludarabine + melphalan

AML = acute myeloid leukemia

sAML = secondary acute myeloid leukemia

ADR = adverse drug reaction

AlloHCT = allogeneic hematopoietic cell transplantation

BM = bone marrow

CYP = cytochrome P450

QTc = corrected QT interval

P-gp = P-glycoprotein

G-CSF = granulocyte colony-stimulating factor

TLS = tumor lysis syndrome

NF = neutropenic fever

ND = newly-diagnosed

R/R = relapsed/refractory

WBC = white blood cell count

ANC = absolute neutrophil count

PLT = platelets

CBC = complete blood count

Hgb = hemoglobin

ORR = overall response rate

DOR = duration of response

NR = no response

OS = overall survival

CR = complete remission

CRi = complete remission with incomplete hematologic recovery

MLFS = morphological leukemia-free state

BMBx = bone marrow biopsy

Background

Cytotoxic and targeted oral chemotherapy represents a new concept in AML

Historically, intravenous cytotoxic chemotherapy-based regimens

Recently, paradigm shift incorporating oral chemotherapy agents

FDA Approval Timeline

MidostaurinEnasidenib

IvosidenibGlasdegibGilteritinib

Azacitidine (oral)Venetoclax

Place In Therapy

Agent Target(s) Treatment Naïve Relapsed/Refractory Maintenance post IC

Midostaurin FLT3-ITD FLT3-TKD

Enasidenib IDH2

Ivosidenib IDH1

Glasdegib

Gilteritinib FLT3-ITDFLT3-TKD

Azacitidine

Venetoclax BCL2

FDA Approved

combined with 7+3

combined with LDAC

combined with HMA/LDAC

Rydapt (midostaurin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2021.Idhifa (enasidenib) [prescribing information]. Summit, NJ: Celgene Corporation; November 2020.Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019.

Daurismo (glasdegib) [prescribing information]. New York, NY: Pfizer Labs; March 2020.Xospata (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; May 2019.Onureg (azacitidine) [prescribing information]. Summit, NJ: Celgene Corporation; March 2021.

Venclexta (venetoclax) [prescribing information]. North Chicago, IL: AbbVie Inc; November 2020.

Notable Drug-Drug Interactions

Agent CYP3A4 inducers/inhibitors

QTc-prolonging agents

P-glycoproteininducers

P-glycoproteininhibitors

Midostaurin

Enasidenib

Ivosidenib

Glasdegib

Gilteritinib

Azacitidine

Venetoclax

Rydapt (midostaurin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2021.Idhifa (enasidenib) [prescribing information]. Summit, NJ: Celgene Corporation; November 2020.Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019.

Daurismo (glasdegib) [prescribing information]. New York, NY: Pfizer Labs; March 2020.Xospata (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; May 2019.Onureg (azacitidine) [prescribing information]. Summit, NJ: Celgene Corporation; March 2021.


Notable Drug-Drug Interactions

Moderate CYP3A4 inhibitors

E.g. fluconazole, isavuconazole

Venetoclax dose 200 mg

Strong CYP3A4 inhibitors

E.g. posaconazole, voriconazole

Venetoclax dose 100 mg

50-70 mg with posaconazole?

Venetoclax

Literature Review

VIALE-A Trial

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial

N = 431 patients with previously untreated AML ineligible for intensive chemotherapy Venetoclax 400 mg PO once daily D1-28 + Azacitidine 75 mg/m2 SQ/IV D1-7 q28d Placebo + Azacitidine 75 mg/m2 SQ/IV D1-7 q28d

OS, CR, CRi Gr3+ thrombocytopenia, neutropenia, NF, infections

DiNardo CD, et al. N Engl J Med. 2020. 383(7):617-629.

Endpoint Ven/Aza Placebo/Aza P-valueOS 14.7 mo 9.6 mo <0.001CR 36.7% 17.9% <0.001CRi 66.4% 28.3% <0.001

VIALE-A Trial

Azole antifungals allowed

WBC < 25 x 109/L prior to treatment initiation 1% incidence of TLS

Venetoclax given D1-28 with all cycles BMBx performed on D28 If in CR/CRi/MLFS hold until ANC >500 or up to 14 days Time to response 1.3 mo vs. 2.8 mo


Venetoclax dose Ven dose with modCYP3A or P-gp inhibitor

Ven dose with strong CYP3A inhibitor

100 mg (C1 D1 only) 50 mg 10 mg200 mg (C1 D2 only) 100 mg 20 mg

400 mg 200 mg 50 mg

VIALE-A Trial

Treatment modifications due to myelosuppression


Cycle CBC on Day 29 Dose ModificationsAfter Cycle 1 CRi Hold chemo until ANC > 500 or up to 14d

After Cycle 2 ANC < 500 x > 1 week* Hold chemo until ANC > 500 or up to 14d

After Cycle 3 ANC < 500 or PLT < 50k Hold chemo until ANC > 500 or PLT > 50k or up to 14d. Reduce VEN to 21d on/7d off

After Cycle 4

ANC > 1000 or PLT > 100k within 14d of Day 29

ANC or PLT not increased by 25% from Day 14 (nadir)

ANC or PLT not increased by 25% from Day 14 (nadir) within 14d of Day 29

Reduce VEN to 21d on/7d off

Reassess CBC every 7d

If no count recovery within 21d of Day 29, check BMBx:-BM cellularity 15-50%: Aza by 50%-BM cellularity <15%: Aza by 67%

*unless due to underlying disease

DEC10-VEN Trial

DEC10-VEN Trial

Phase 2, single center trial

N = 168 patients with ND or R/R AML Venetoclax 400 mg PO once daily D1-28 + Decitabine 20 mg/m2 IV D1-10 q28d Cycle 2 on Venetoclax 400 mg PO once daily D1-21 q28d Once in CR/CRi Decitabine 20 mg/m2 IV D1-5 q28d

Grade 3-4 ADRs: infection (47%), NF (29%)

DiNardo CD, et al. Lancet Haematol. 2020. 7(10):e724-e736.

Endpoint Overall ND ND sAML R/R AML R/R sAMLORR 74% 89% 80% 62% 61%OS --- 18.1 mo 7.8 mo 7.8 mo 6.0 mo

DOR --- NR 5.1 mo 16.8 mo NR

DEC10-VEN Trial

Azole antifungals allowed

WBC < 10 x 109/L prior to treatment initiation 2% incidence of TLS

BMBx on D21 hold VEN if aplasia or <5% blasts to allow for count recovery

Once ANC ≥ 500/μL and PLT >50 x 109/L, resume treatment

Time to response ~1.5 mo


Venetoclax dose VEN dose with modCYP3A inhibitor

VEN dose with strong CYP3A inhibitor

100 mg (C1 D1 only) 100 mg 100 mg200 mg (C1 D2 only) 200 mg 100 mg

400 mg 200 mg 100 mg

DEC10-VEN Trial


Dose Level DEC dose (mg/m2) VEN dose (mg) VEN duration0 (starting dose) 20 400 21 days

-1 15 200 21 days-2 10 200 14 days

No treatment delay Delay treatment until count recovery then resume at same doses If delayed >14 days (>D42), delay treatment until

count recovery then resume with dose adjustments for DEC, VEN, or both per table below

If D29 ANC <500/μL and PLT <50 x 109/L

Evidence of AML No evidence of AML

How I Treat AML in the Era of New Drugs

Post-induction BMBx on D21-28 of cycle 1 If > 5% blasts proceed with next cycle without delay If < 5% blasts hold VEN and resume at full dose once ANC > 500/μL and PLT > 50 x

109/L (hematologic recovery). G-CSF may be used.

Subsequent cycles (< 5% BM blasts) If ANC < 500/μL for >7d or severe complications hold VEN and start G-CSF until ANC recovery

Do not dose-reduce VEN to manage myelosuppression

If hematologic recovery takes >14d after holding VEN resume once hematologic recovery achieved with stepwise VEN duration reduction (28d 21d 14d) May reduce HMA dose based on BM cellularity if responding with delayed/lack of hematologic recovery 15-30% cellularity decrease HMA by 50% <15% cellularity decrease HMA by 67%

Consider G-CSF prophylaxis after HMA (D8) or LDAC (D11)DiNardo CD, et al. Blood. 2020. 135(2):85-96.

Venetoclax Package Insert


WBC < 25 x 109/L prior to treatment initiation

Only available as 10 mg, 50 mg, or 100 mg tablets

*Continue until progression/toxicity**Monitor closely for hematologic toxicities and TLS. Resume previous VEN dose 2-3d after CYP3A4 inhibitor discontinuation

Cycle 1 VEN dose VEN dose with mod CYP3A or P-gp inhibitor**

VEN dose with strongCYP3A inhibitor**

VEN dose with posaconazole**

Day 1 100 mg -No specific ramp-up recommendations

- VEN dose by at least 50%

10 mg 10 mgDay 2 200 mg 20 mg 20 mgDay 3 400 mg 50 mg 50 mg

Day 4 on* 400 mg (HMA)600 mg (LDAC) 100 mg 70 mg

Venetoclax Package Insert


Treatment modifications due to myelosuppressionANC < 500 or PLT <

25,000 Management*

Prior to remission Don’t interrupt VEN/HMA/LDAC BMBx recommended

1st occurrence after remission and lasting > 7d

Delay next cycle and monitor CBCOnce ANC > 1,000 resume regimen at same doses

Subsequent occurrences after remission and lasting

> 7d

Delay next cycle and monitor CBCOnce ANC > 1,000 resume regimen and reduce VEN

duration by 7d

*Consider supportive care (e.g. antimicrobial prophylaxis, G-CSF), as clinically necessary for all situations

Pharmacokinetic Study

Pharmacokinetic analysis of 12 patients

DEC 20 mg/m2 IV on D1-5 and VEN ramp up to 400 mg once daily through D20

Posaconazole 300 mg once daily with VEN 50 mg or 100 mg on D21-28

Blood samples collected before VEN and up to 24h after VEN on D20 and D28

Agarwal SK, et al. Clin Ther. 2017. 39:359-367.

Compared to VEN 400 mg

alone

Endpoints VEN 50 mg +Posaconazole

VEN 100 mg +Posaconazole

Mean VEN Cmax increased 53% increased 93%Mean AUC0-24 increased 76% increased 155%

With concomitant posaconazole… Both VEN 50 mg and 100 mg were well-tolerated Dose-reduce VEN by at least 75%

Retrospective Study

Retrospective, single-center analysis

N = 64 patients with ND AML in CR/CRi after 1 cycle of VEN + HMA

VEN given D1-28; stopped if D21 BMBx showed aplasia or < 5% blasts

Primary outcome Time to count recovery (ANC > 500-1000/μL and PLT >50-100 x 109/L)

Rausch CR, et al. Cancer. 2021. 0:1-11.

VEN dose N (%)No azole 400 mg 17 (27%)

Moderate CYP3A4 inhibitor 200 mg 21 (33%)Strong CYP3A4 inhibitor 100 mg 26 (41%)

Retrospective Study

Rausch CR, et al. Cancer. 2021. 0:1-11.

Selected endpoints (median) Voriconazole Posaconazole P-valueDays to ANC > 500/μL 35 35 NS

Days to ANC > 1000/μL 38 35 NSDays to PLT > 50 x 109/L 28 25 < 0.05Days to PLT > 100 x 109/L 32 26 NS

With 1 cycle of HMA + VEN…Posaconazole doesn’t prolong time to count recovery compared to

other azole antifungalsVEN 100 mg can be given safely with either posaconazole or

voriconazole

Patient Case

Patient Case - Diagnosis

GG is a 70 yo male with relapsed AML s/p alloHCT who presents to clinic with the following:

Lab ResultWBC 15,000/mcLANC 0/mcLPLT 9,000/mcLHgb 8.1 g/dL

Peripheral blasts 68%Uric acid 6.4 mg/dL

BMBx hypocellular with 70-80% blasts c/w relapsed AML

Patient Case – Cycle 1

Azacitidine + venetoclax selected Since WBC > 10,000-25,000/mcL started on cytoreduction with hydroxyurea x 3 days Since ANC < 500/mcL started on fluconazole, acyclovir, and levofloxacin prophylaxis Since concomitant fluconazole VEN 100 mg on D1, 200 mg once daily thereafter

Cycle 1 Day 1 (C1D1) of AZA 75 mg/m2 x 7d + VEN 200 mg once daily q28d


Peripheral blasts 75%Uric acid 4.1 mg/dL

Patient Case – Cycle 1-2

C1D29 – VEN held due to pancytopenia pending BMBx pathology

C1D30 – AZA cycle 2 started, VEN held x 1 week Antimicrobial prophylaxis continued

Lab ResultWBC 590/mcLANC 10/mcLPLT 24,000/mcLHgb 7.2 g/dL

Peripheral blasts 0%BMBx normocellular with 5% blasts


C2D31 – Patient seen in clinic prior and started on cycle 3

C2D31 – AZA + VEN cycle 3 started. VEN frequency decreased to D1-21 q28d per MD discretion since patient held x 1 week at start of cycle 2 Antimicrobial prophylaxis continued


Peripheral blasts 0%


C3D28 – Patient seen in clinic prior to cycle 4. BMBx performed to reassess disease and cycle 4 delayed

C3D42 – Counts recovered. AZA + VEN cycle 4 started. VEN frequency decreased to D1-14 q28d since patient neutropenic on D28 Antimicrobial prophylaxis continued


Peripheral blasts 0%BMBx hypocellular with 5% blasts


C4D30 – Patient seen in clinic prior to cycle 5. Cycle 5 delayed due to pancytopenia

C4D44 – Counts recovered. AZA + VEN cycle 5 started. AZA decreased from 7d to 5d, VEN decreased from D1-14 to D1-10, and cycle prolonged to q35d since patient pancytopenic on D30 Antimicrobial prophylaxis continued




VEN held since C5D10 and Cycle 6 delayed due to persistent pancytopenia

Interim BMBx – variably cellular with 3-4% blasts

Cycle 6 resumed after 7 week delay. AZA continued on D1-5 q35d, VEN discontinued Antimicrobial prophylaxis continued


C6D36 – Patient seen in clinic prior to cycle 7. Cycle 7 delayed due to pancytopenia

C6D50 – Still pancytopenic, but now has 8% peripheral blasts, so Cycle 7 resumed. AZA frequency increased to D1-7, VEN 200 mg D1-28 resumed, and cycle length decreased to q28d Antimicrobial prophylaxis continued

Lab ResultWBC 1,370/mcLANC 80/mcLPLT <5,000/mcLHgb 8.5 g/dL



C7D29 – Patient seen in clinic prior to cycle 8. Cycle 8 initiated with no dose changes

C8D29 Still pancytopenic despite peripheral blast clearance BMBx – recurrent AML with 22% blasts Chemo regimen changed to gemtuzumab ozogamicin (GO) Admitted with NF and progressive disease. Discharged with home hospice and expired 20

days after starting GO



Key Takeaways

Check D21-28 BMBx with cycle 1 If in CR/CRi/MLFS hold VEN and delay cycle 2 until ANC > 500, PLT > 50 If > 5% blasts continue VEN and start cycle 2 without delay

Once in CR, low threshold to reduce VEN to D1-21 regardless of cytopeniasresulting in treatment delays

If hematologic recovery takes >7-14d after holding VEN, consider BMBx to assess for relapse then proceed with stepwise reductions Shorten VEN duration (28d 21d 14d) Decrease HMA dose and/or consider decreasing number of HMA doses per cycle Consider prolonging treatment cycle (28d 35d 42d)

UK Markey Cancer Center Approach

Learning Assessment

QUESTION #1

JW is a 67 yo male with relapsed FLT3-ITD mutated AML s/p induction with 7+3+midostaurin, consolidation with HiDAC + midostaurin x 2 cycles and FluMel alloHCT. The team decides to start him on gilteritinib. What antifungal prophylaxis agent would you NOT recommend?

A. VoriconazoleB. FluconazoleC. IsavuconazoleD. Posaconazole

QUESTION #2

A 73 yo female with no significant past medical history is admitted to the inpatient hematology service. She is found to have newly diagnosed de novo AML with normal cytogenetics, no gene mutations, and WBC = 57 x 109/L. The team does not consider her to be a candidate for intensive induction and wants to start her on a HMA + VEN. The patient is currently on antimicrobial prophylaxis with posaconazole, acyclovir, and levofloxacin. Which of the following is your recommendation to the team?

A. Start AZA 75 mg/m2 IV D1-7 + VEN 400 mg PO once dailyB. Start hydroxyurea until WBC < 10-25 x 109/L then begin AZA 75 mg/m2 IV D1-7 + VEN 50-100

mg PO once dailyC. Start DEC 20 mg/m2 IV D1-10 + VEN 200 mg PO once dailyD. Start hydroxyurea until WBC < 10-25 x 109/L then begin DEC 20 mg/m2 IV D1-10 + VEN 200 mg

PO once daily

QUESTION #3

This patient is started on hydroxyurea until WBC < 10-25 x 109/L then started on AZA 75 mg/m2 IV D1-7 + VEN 100 mg PO once daily. Her D28 BMBx indicates aplasia with 2% blasts and her ANC = 0/μL. What is your recommendation to the team?

A. Stop VEN and delay cycle 2 until ANC > 500/μL or up to 14 daysB. Continue VEN and repeat BMBx on D35C. Stop VEN and delay cycle 2 by 7 days regardless of ANC at that timeD. Continue VEN and start cycle 2 without delay

Oral Chemotherapy Clinical Pearls in AML

Rob Walchack, PharmD, BCOP

Hematology/Cellular Therapy Clinical Pharmacy Specialist

UK HealthCare

September 17, 2021

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Oral Chemotherapy Clinical Pearls in AML