Nuevas opciones de Tratamiento en Leucemia Linfática Aguda - Dr. Gustavo Milone

Nuevas Opciones de Tratamiento en la Leucemia Linfocítica Aguda.

VII Congreso Peruano de Hematología. V Simposio Latinoamericano de SMD. 20 al 22 de Octubre de 2016, Lima Perú Dr Gustavo Milone GATLA gustavomilone@gmail.com

Enfermedad Mínima Residual en LLA § Las células leucémicas estan presentes en niveles por debajo de la detección por los métodos morfológicos convencionales[1] § La EMR es útil para la toma de decisiones terapéuticas en pacientes en RC § Medida por citometría de flujo, PCR para rearreglos específicos de Ig o TCR, o NGS § La correlación entre la detección temprana de EMR y recaidas precoces esta bien establecida en estudios de pacientes pediátricos y recientes de adultos con LLA [2]

1. NCCN. Clinical practice guidelines in oncology: acute lymphoblastic leukemia. v.2.2015.

2. Bassan R, et al. Blood. 2009;113:4153-4162.

§ Adult pts with B- or T-cell precursor ALL (N = 280) § Phase A: induction/consolidation therapy (8 chemotherapy blocks over 25 wks; NILG-ALL 09/00 protocol)

Cumulative Survival

Treatment Outcomes According to MRD Status in Adult ALL

– MRD pos: allogeneic HCT or intensification/maintenance therapy – MRD unknown: MRD-neg treatment if conventional SR; MRD-pos treatment if conventional HR/VHR

Bassan R, et al. Blood. 2009;113:4153-4162.

Cumulative Survival

– MRD neg: maintenance therapy

MRDneg (n = 58)

0.75 0.50

MRDu/k (n = 30)

0.25

MRDpos (n = 54)

0

§ Phase B: treatment by MRD status

DFS by MRD Status

1.00

0

12

24

36 48 60 72 84 Mos DFS by Clinical Risk in MRD-Neg Group 1.00 VHR (n = 5) HR (n = 18) SR (n = 35)

0.75 0.50 0.25 0

0

12

24

36 48 Mos

60

72

84

Tratamiento de la LLA Ph Negativa

Tratamiento de Adultos con LLA: Estado Actual § No existe un tratamiento estandar en primera línea[1] § Terapia de Inducción – RC alta tasa (90%)

§ Post-remisión – > 50% tasa de fallos (mayoria recaidas)[1,2] – TCP Alogénico en 1 RC rol incierto[3]

§ Recaida – Baja tasa de respuesta (< 45%) y muy corta supervivencia[4] – No existe quimioterapia estandar[1] 1. NCCN. Clinical practice guidelines in oncology: acute lymphoblastic leukemia. v.2.2015.

2. Tavernier E, et al. Leukemia. 2007;21:1907-1914.

3. Rowe JM. Biol Blood Marrow Transplant. 2011;17:S76.

4. O’Brien S, et al. Cancer. 2008; 113: 3186-2191.

Induction, Consolidation, and Maintenance Therapy for Ph-Neg Pts Ph- ALL Pt

Induction

AYA (15-39 yrs) Adult (40-64 yrs or no substantial comorbidities) Adult (≥ 65 yrs or substantial comorbidities)

Pediatric-inspired regimen Clinical trial OR

Multiagent chemotherapy Multiagent chemotherapy OR corticosteroids

Consolidation* Continue multiagent chemotherapy† OR Consider allogeneic HCT if donor available‡ Chemotherapy

*For pts with CR; all other should be treated for relapsed/refractory disease. Pts should also be monitored for MRD after induction therapy. †Especially for MRD-neg pts. ‡Especially for MRD-pos pts and pts with high WBC or poor risk cytogenetics.

§ Following successful consolidation therapy; all pts should continue on maintenance therapy consisting of MTX QW + 6-mercaptopurine QD + vincristine/prednisone pulses QM for 2-3 yrs § All pts should receive CNS prophylaxis NCCN. Clinical practice guidelines in oncology: acute lymphoblastic leukemia. v.2.2015.

Induction Therapy Options for Ph-Negative ALL Adult Pts (40 Yrs of Age or Older)

Pediatric-Inspired Protocols for AYA Pts (15-39 Yrs of Age)

CALGB 8811 Larson: daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide

GRAALL-2003: daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide (pts 60 yrs of age or younger)

Linker 4-drug: daunorubicin, vincristine, prednisone, pegaspargase

CCG-1961: daunorubicin, vincristine, prednisone, pegaspargase (pts 21 yrs of age or younger)

Hyper-CVAD Âą rituximab: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose MTX and cytarabine; Âą rituximab for CD20+

COG AALL-0434 with nelarabine (for T-ALL): daunorubicin, vincristine, prednisone, pegaspargase; + nelarabine for consolidation regimen (ongoing study)

MRC UKALLXII/ECOG2993: daunorubicin, vincristine, prednisone, pegaspargase (phase I); cyclophosphamide, cytarabine, 6-mercaptopurine (phase II)

DFCI ALL (based on DFCI Protocol 00-01): doxorubicin, vincristine, prednisone, high-dose MTX, pegaspargase (ongoing study in pts younger than 50 yrs of age) CALGB 10403: daunorubicin, vincristine, prednisone, pegaspargase (ongoing study in pts < 40 yrs) PETHEMA ALL-96: daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide (pts younger than 30 yrs of age)

NCCN. Clinical practice guidelines in oncology: acute lymphoblastic leukemia. v.2.2015.

USC ALL (based on CCG-1882): daunorubicin, vincristine, prednisone, MTX with augmented pegaspargase (pts 18-57 yrs)

Pediatric or Pediatric-Inspired Regimens in Recent Adult ALL Clinical Trials Regimen True pediatric § DFCI[1] § CALGB 10403[2] Pediatric inspired § PETHEMA[3] § GRAALL-2003[4] § USC[5]

Upper Age of Population, Yrs

OS Rate (2-7 Yrs), %

50 39

67 79

30 15-45 46-60 57

69 64 47 51

1. DeAngelo DJ, et al. Leukemia. 2015;29:526-534.

2. Stock W, et al. ASH 2014. Abstract 796.

3. Ribera JM, et al. J Clin Oncol. 2008;26:1843-1849.

4. Huguet F, et al. J Clin Oncol. 2009;27:911-918.

5. Douer D, et al. J Clin Oncol. 2014;32:905-911.

Pediatric-Inspired CT vs Allogeneic HCT for Ph-Negative Adult ALL in CR1 Retrospective analysis of Ph-negative adult pts* in CR1 who had undergone allogeneic HCT (N = 422) or chemotherapy with DFCI ALL pediatric regimen (N = 108) OS

0.8 0.6 0.4

HR: 2.86 (95% CI: 1.88-4.34; P < .0001)

0.2 0

0

0.8 0.6

HR: 7.48 (95% CI: 3.28-17.05; P < .0001)

0.4 0.2 0

0

12 24 36 48 60 72 Mos Since Remission *18-50 yrs of age.

Seftel MD, et al. ASH 2014. Abstract 319.

0.8 0.6 0.4

HR: 3.11 (95% CI: 2.08-4.66; P < .0001)

0.2 0

72

Treatment-Related Mortality

1.0 Probability

12 24 36 48 60 Mos Since Remission

Disease-Free Survival

1.0 Probability

Probability

1.0

0

Chemo (n = 107) HCT (n = 422) 1.0 Probability

§â&#x20AC;Ż

12 24 36 48 60 Mos Since Remission

72

Relapse

0.8 0.6

HR: 1.74 (95% CI: 1.07-2.82; P < .0252)

0.4 0.2 0

0

12 24 36 48 60 Mos Since Remission

72

Effect of Allogeneic HCT on ALL Outcomes According to MRD Response

Probability of Survival

§ Ph-negative high-risk pts (55 yrs of age or younger) in CR1 after previous enrollment in GRAALL-2003/2005 were treated with or without allogeneic HCT (N = 522) OS 1.00 0.80 0.60 0.40 0.20 0

MRD1 < 10-3, no HCT MRD ≥ 10-3, no HCT

0

1

Dhédin N, et al. Blood. 2015;125:2486-2496

MRD1 < 10-3, HCT MRD ≥ 10-3, HCT

2

Yrs

3

4

5

GRAALL-R: Rituximab + Pediatric-Inspired Chemotherapy for Adult ALL §

Multicenter, randomized phase III study from 2005-2014[1] – CD20 expressed in 30% to 40% of BCP-ALL pts, associated with poor outcomes[2,3] – Rituximab: anti-CD20 antibody CD20+ Ph- tx-naive BCP-ALL pts 18-59 yrs of age with ≥ 20% CD20+ blasts and no other current/recent malignancies (N = 220)

Pediatric-Inspired Chemo + Rituximab IV 375 mg/m2 16-18 infusions (n = 105) Pediatric-Inspired Chemotherapy (n = 104)

§

Allogeneic HCT offered in CR1 to pts with ≥ 1 high-risk criteria

§

Primary endpoint: EFS

§

Median follow-up: 30 mos

§

Baseline characteristics generally well balanced between groups – Allogeneic HCT in CR1 occurred more frequently in rituximab group vs control (34% vs 20%, P = .03)

1. Maury S, et al. ASH 2015. Abstract 1.

2. Thomas DA, et al. Blood. 2009;113:6330-6337.

3. Maury S, et al. Haematologica. 2010;95:324-328.

GRAALL-R: Efficacy Rituximab (n = 105)

No Rituximab (n = 104)

P Value

CR in 1 induction course

95 (91)

91 (88)

.52

CR

97 (92)

94 (90)

.63

Resistant disease

1 (1)

1 (1)

.99

Induction deaths

7 (7)

9 (9)

.61

Postinduction MRD < 10-4

32/49 (65)

22/36 (61)

.82

Postconsolidation MRD < 10-4

42/46 (91)

28/34 (82)

.31

Response, n (%)

Rituximab vs No Rituximab Outcome

Probability, %

HR (95% CI)

Adjusted HR* (95% CI)

EFS

65 vs 52

0.66 (0.45-0.98; P = .038)

0.59 (0.37-0.93; P = .021)

OS

71 vs 64

0.70 (0.46-1.07; P = .095)

0.55 (0.34-0.91; P = .018)

Relapse†

18 vs 32

0.52 (0.31-0.89; P = .017)

0.49 (0.27-0.89; P = .018)

*Adjusted for HCT during CR1. †Cumulative incidence of relapse.

Maury S, et al. ASH 2015. Abstract 1.

Recomendaciones para Pacientes con LLA Ph-Negativa Recaidos/Refractarios en adolescentes y adultos jovenes § Considerar ensayo clínico § Quimioterapia – Clofarabina- o citarabina dentro de los esquemas – Alquilantes dentro de los esquemas – Nelarabina (para T-ALL) – Hyper-CVAD aumentado – Vincristinea sulfato liposomal

§ Inmunoterapia – Blinatumomab (para LLA-B)

§ TCP Alogénico (luego de RC)

Chemotherapeutic Efficacy in Relapsed/ Refractory Adult ALL Setting

CR Rates, %

Median OS, Mos

First relapse[1-5]

30-45

5-9

Primary refractory disease, short CR,* or relapse after HCT[2,3]

20-30

3-6

Second relapse[6-7]

18-20†

3-4.6

*CR < 12 mos. †CR + CRi.

1. Fielding AK, et al. Blood 2007;109:944-950.

2. Gökbuget N, et al. Blood. 2012;120:2032-2041.

3. Kantarjian HM, et al. Blood. 2010;116:5568-5574.

4. Oriol A, et al. Haematological. 2010;95:589-596.

5. Tavernier E, et al. Leukemia. 2007;21:1907-1914.

6. O’Brien S, et al. Cancer. 2008; 113:3186-2191.

7. O’Brien et al. J Clin Oncol. 2013;31:676-683.

Blinatumomab §

Mechanism:

T cell

– Bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19positive cells, resulting in serial lysis[2] – CD19: highly specific B-cell marker expressed throughout B-cell development and in > 90% of B-cell lineage cancers[3]

§

Indicated for treating Ph-negative relapsed/refractory B-cell precursor ALL (approved December 2014)[4]

§

Administration: 28 µg/day continuous IV infusion over 28 days

§

Boxed warnings: cytokine release syndrome and neurological toxicities

1. Gökbuget N, et al. ASH 2014. Abstract 379.

2. Bargou R, et al. Science. 2008;321:974-977.

3. Raponi S, et al. Leuk Lymphoma. 2011:52;1098-1107.

4. Blinatumomab [package insert]. December 2014

CD3

TCR

Blinatumomab CD19

B-precursor ALL cell

Blinatumomab for Relapsed/Refractory, B-Precursor, Ph-Negative ALL § Multicenter, single-arm, open-label phase II study Pts with Ph-, B-cell precursor ALL who were 18 yrs of age or older and were refractory after induction, had relapsed within 12 mos of CR1 or HCT, or were relapsed/refractory after salvage tx (N = 189)

Blinatumomab 9 µg/day CIV for 1 wk,* then 28 µg/day to 4 wks, then 2 wks off; up to 5 cycles

Dexamethasone premedication was required 1 h before tx initiation in each cycle. Pts who achieved CR/CRh after 2 cycles could receive 3 more cycles. *During cycle 1.

§ Primary endpoint: CR and CRh within the first 2 cycles § Median age: 39 yrs Topp MS, et al. Lancet Oncol. 2015;16:57-66.

Blinatumomab in Relapsed/Refractory ALL: Efficacy Outcome

All Pts (N = 189)

CR or CRh in first 2 cycles, %

43

CR in first 2 cycles, %

33

MRD negativity in first 2 cycles, %*

82

Median OS, mos § All pts § MRD-negative CR § MRD-positive CR

6.1 11.5 6.7

Median RFS, mos § CR + CRh § CR § CRh

5.9 6.9 5.0

Allogeneic HCT, %* § After CR § After CRh

40 44 22

100-day mortality after allogeneic HCT, %

11

*Of pts in CR or CRh. Topp MS, et al. Lancet Oncol. 2015;16:57-66.

Blinatumomab in Relapsed/Refractory ALL: Notable AEs AE, % (N = 189)

Any Grade

Grade 1/2

Grade ≥ 3

Fever

60

53

7

Febrile neutropenia

28

3

25

Neutropenia

17

2

16

Anemia

20

6

14

Cytokine release syndrome

NA

NA

2

Neurologic events § Tremor § Dizziness § Confusion § Encephalopathy § Ataxia § Somnolence § Aphasia § Change in mental status

52 17 14 7 5 5 5 4 4

39 17 13 6 2 3 4 3 3

13 <1 <1 2 3 2 <1 1 1

§ Treatment-related deaths: 2% (sepsis [n = 2]; Candida infection [n = 1]) Topp MS, et al. Lancet Oncol. 2015;16:57-66.

Blinatumomab: Boxed Warning Toxicities § Cytokine release syndrome – Systemic inflammatory response; ranges from mild to severe, life threatening – Can lead to vascular leak, fever, hypotension, respiratory and renal insufficiency, cytopenias, coagulopathy

§ Neurological changes – Can include delirium, confusion, global encephalopathy, aphasia, seizures or seizurelike effects Blinatumomab [package insert]. December 2014.

Maude SL, et al. N Engl J Med. 2014;371:1507-1517.

TOWER: Phase III Trial of Blinatumomab for Relapsed/Refractory ALL § Multicenter, randomized, open-label phase III study § Primary endpoint: OS Blinatumomab 9 µg/day CIV for 1 wk,* then 28 µg/day to 4 wks, then 2 wks off

Pts with relapsed or refractory Ph-, B-precursor ALL

Standard Chemotherapy Investigator’s choice†

*During cycle 1. †Options

include: § FLAG ± anthracycline-based regimen § HiDAC-based regimen ± anthracycline § High-dose methotrexate–based regimen § Clofarabine- or clofarabine-based regimens ClinicalTrials.gov. NCT02013167.

Blinatumomab in MRD-Positive B-Cell Precursor ALL § International, multicenter, open-label phase II study from 2010-2013 § Primary endpoint: achieving MRD < 10-4 in cycle 1 CD19+ BCP ALL pts 18 yrs of age or older with < 5% BM blasts, MRD ≥ 10-3 after ≥ 3 chemotherapies, and no prior alloSCT, CNS/extramedullary involvement, or Ph+ ALL eligible for TKIs (N = 116)

Cycle 1* Blinatumomab 15 µg/m2 QD CIV *28 days on tx, 14 days off.

Gökbuget N, et al. ASH 2015. Abstract 680.

Pts with MRD response received ≤ 3 additional cycles and/or alloSCT (eligible pts); tx discontinuation upon hematologic relapse

Followed for 2-yr efficacy, survival

Blinatumomab in MRD-Positive B-Cell Precursor ALL: Efficacy Blinatumomab (n = 110)

MRD Complete vs Incomplete, P Value

Median OS § MRD complete responder § MRD incomplete responder

36.5 38.9 12.5

.002

Median RFS § CR1 § CR2/CR3 § MRD complete responder § MRD incomplete responder

18.9 24.6 11.0 23.6 5.7

Median duration of remission § MRD complete responder § MRD incomplete responder

NR NR 17.2

Outcome, Mos

§

Median follow-up: 30 mos

§

Complete MRD response: 80%

§

Transplant realization rate: 72%

Gökbuget N, et al. ASH 2015. Abstract 680.

.003

.049

Blinatumomab in MRD-Positive B-Cell Precursor ALL: Safety Characteristic, n (%)

AE (N = 116)

Tx-Related AE (N = 116)

Any AE § Serious § Grade 3 § Grade 4

116 (100) 73 (63) 38 (33) 31 (27)

112 (97) 60 (52) 34 (29) 25 (22)

2 (2)

1 (< 1)

AE-related tx interruption

36 (31)

33 (28)

AE-related tx discontinuation

20 (17)

14 (12)

Death

§ Neurotoxicity was the most clinically relevant AE – 53% (61/116) of pts experienced a neurologic event, primarily tremor (30% pts) and aphasia (15% pts) – Grade 3/4 neurologic AEs caused treatment interruptions/discontinuations in 12 pts (10%) Gökbuget N, et al. ASH 2015. Abstract 680.

ALCANTARA: Blinatumomab for Relapsed/Refractory Ph-Positive ALL § Phase II single-arm study Primary Endpoint Assessed During First 2 Cycles Adults with R/R Ph+ B-precursor ALL; ECOG PS 0-2; > 5% BM blasts; failed TKI (N = 45)

Blinatumomab IV 9 µg/day x 1 wk 28 µg/day x 3 wks (cycle 1) 28 µg/day x 4 wks (cycle 2) (4 wks on, 2 wks off)

Consolidation: Blinatumomab IV 28 µg/day x 4 wks ≤ 3 cycles (4 wks on, 2 wks off)

§ Primary endpoint: CR/CRh during first 2 cycles § Secondary endpoints: best CR, MRD, RFS, OS, allogeneic HCT rate, and safety Martinelli G, et al. ASH 2015. Abstract 679. ClinicalTrials.gov. NCT02000427.

Follow-up at 30 days and ≤ 18 mos

ALCANTARA: Efficacy Parameter

Response, %

Primary endpoint CR/CRh (first 2 cycles) § T315l mutation § ≥ 2 prior 2+ gen TKI § Prior ponatinib treatment

36 40 41 35

Secondary endpoints Best response (first 2 cycles) § CR § CRh § CRi (not including CRh)

31 4 4

Complete MRD response* § MRD response in pts with ABL-kinase mutations

88 100

Proceeded to allogeneic HCT*

25

*In pts with CR/CRh.

§ Median RFS: 6.7 mos (95% CI: 4.4-NE) § Median OS: 7.1 mos (95% CI: 5.6-NE) Martinelli G, et al. ASH 2015. Abstract 679.

Ongoing Blinatumomab Trials in Adult ALL Study Description

Pt Population

Phase III ECOG 1910[1]

Newly-diagnosed adult Ph-negative B-lineage ALL

Phase II SWOG 1318[2]

Pts aged 65 yrs or older with newly diagnosed Phpositive ALL

Estimated Enrollment

Study Arms

Primary Endpoint

360

Induction chemotherapy Âą blinatumomab

OS

44

Blinatumomab and combination chemotherapy or dasatinib, prednisone, and blinatumomab

Toxicity, OS

1. ClinicalTrials.gov. NCT02003222. 2. ClinicalTrials.gov. NCT02143414.

Inmunoterapia Investigacional en el Tratamiento de la LLA Precursores B

CAR T-Cell Therapy § Utilizes modified T cells to eradicate tumor cells

T cell from pt

§ Procedure: 1.

Remove pt’s T cells from blood

2.

CAR T-cell creation: “teach” T cells to recognize tumor cells expressing a CD19 antigen using lentiviral-vector technology[1-3] –

3.

CAR T cells include genetically engineered antigen receptors that combine the anti-CD19 single chain variable fragment (scFV) of an antibody with intracellular signaling domains of T cells

Expand engineered CAR T cells in laboratory and reinfuse back into pt

1. Grupp S, et al. ASH 2014. Abstract 380. 2. Maude SL, et al. Blood.

2015;125:4017-4023. 3. Kalos M, et al. Immunity. 2013;39:49-60.

Cells genetically engineered to express CD19-targeting CAR

CD19 Leukemic cell

Summary of CD19 CAR T-Cell Efficacy in Relapsed/Refractory Adult ALL CAR T-Cell Product

JCAR015 (19-28z)[1]

CTL019 (19-4-1BBz)[2] JCAR017 (19-4-1BBz)[3]

Median Age, Yrs (Range)

N

CAR T-Cell Dose

Efficacy § CR, % • Overall: 82 • MRD neg: 83 • Ph pos: 93 • Ph neg: 77 § Median OS, mos • Overall: 9.0 • MRD neg: NR • MRD pos: 6.0

45 (22-74)

46

1 or 3 x 106 cells/kg

NA

12

NA

§ CR: 89%

NA

20

2 x 105 to 2 x 107 cells/kg

§ CR: 83%

1. Park JH, et al. ASH 2015. Abstract 682.

2. Frey NV, et al. ASH 2014. Abstract 2296.

3. Cameron JT, et al. ASCO 2015. Abstract 3006.

Summary of CD19 CAR T-Cell CRS and Neurologic Toxicities CAR T-Cell Product

N

Severe CRS,* %

Grade 3/4 Neurotoxicity, %

Grade 5 Toxicity, %

JCAR015 (19-28z)[1]

46

24

28

6†

CTL019 (19-4-1BBz)[2]

12

92

NA

25‡

JCAR017 (19-4-1BBz)[3]

20

NA§

NA

NA§

*Requiring vasopressors and/or mechanical ventilation for hypoxia. †Sepsis/multiorgan failure, n = 2; seizure, n = 1. ‡3 pts with refractory CRS and concomitant infection. §1 pt who received the highest cell dose died of complications associated with severe CRS.

1. Park JH, et al. ASH 2015. Abstract 682.

2. Frey NV, et al. ASH 2014. Abstract 2296.

3. Cameron JT, et al. ASCO 2015. Abstract 3006.

Conclusiones § Regimenes pediátricos o inspirados en protocolos pediátricos constituyen hoy el estandar de tratamiento de inducción para pacientes adolescentes jovenes y adultos. § La inmunoterapia tiene un rol en el escenario de pacientes recaidos/refractarios.

– Blinatumomab (aprovado para el tratamiento de LLA Ph-negativa recaida/refractaria de precursores B) y células CART modifican las células T para identificar y eliminar las células LLA-B.