managing t-cell lymphoma

PTCLOK, Now What?

Steven M. Horwitz M.D.Assistant AttendingLymphoma Service

Memorial Sloan-Kettering Cancer Center

Peripheral T-cell Lymphoma-NOS

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Prognosis: Overall and Failure-free Survival

Armitage J, et al. J Clin Oncol. 2008;26:4124–4130, International T-cell Classification Project

Current Problems with PTCL

Current Problems Confusing terminology/ Difficult Diagnosis Poor Prognosis Results with “Standard” Therapy

Thinking about solutions High-Dose therapy New (or not so new) Drugs Ways to move forward

WHO 2008 CLASSIFICATION OF MATURE T/NK-CELL NEOPLASMS

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Chronic lymphoproliferative NK cells

Aggressive NK-cell leukemia

Adult T-cell lymphoma/leukemia

Systemic EBV-positive T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Enteropathy-type intestinal T-cell lymphoma

Hepatosplenic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL)

Anaplastic large cell lymphoma, ALK-positive

Anaplastic large cell lymphoma, ALK-negative

Peripheral T-cell lymphoma, NOS

Mycosis fungoides

Sezary syndrome

Primary cutaneous CD30+ lymphoproliferative

Primary cutaneous anaplastic large cell

Lymphomatoid papulosis

Borderline lesions

Subcutaneous panniculitis-like T-cell

Primary cutaneous gamma-delta T-cell

Hydroa vacciniforme lymphoma

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell

Primary cutaneous small/medium CD4+ T-cell lymphoma (provisional)

“Systemic T-cell Lymphoma”Peripheral T-cell lymphoma NOS

Angioimmunoblastic T-cell lymphoma

Anaplastic Large Cell-ALK-1 negative

Anaplastic Large Cell-ALK-1 positive

Enteropathy-type intestinal lymphoma

Extranodal NK/T-cell lymphoma-nasal

Adult T-cell leukemia/lymphoma

Hepatosplenic T-cell lymphoma (may be derived from an immature T-cell)

Peripheral T-cell Lymphomas, PTCL refers to mature T-cell lymphomas (Pathology Definition)

“CTCL”Mycosis FungoidesSezary syndrome

Subcutaneous panniculitis-like Primary cutaneous ALCLLymphomatoid papulosis

Primary cutaneous small/medium CD4+ T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell

lymphoma

Cancers of Immature T-cells lymphoblastic lymphoma and acute

lymphoblastic leukemia

Expert Agreement: Consensus Diagnosis

ALCL, ALK+ 97% PTCL, unspecified 75%

ATLL 93% Panniculitis-like 75%

Nasal NK/T-cell 92% ALCL, ALK- 74%

Angioimmunoblastic 81% Hepatosplenic 72%

Enteropathy-type 79% Cutaneous ALCL 66%

Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.

Expert Agreement Upon Re-review

Overall agreement 81%

Reviewer 1 67%

Reviewer 2 74%

Reviewer 3 83%

Reviewer 4 87%

Reviewer 5 95%

Data from Dennis Weisenberger, Int PTCL Project

International PTCL StudyMajor NHL Types by Region

Percent NA EU FE

PTCL, unspecified 34.4 34.3 22.4

Angioimmunoblastic 16.0 28.7 17.9

Anaplastic, ALK+ 16.0 6.4 3.2

Anaplastic, ALK- 7.8 9.4 2.6

NK/T-cell 5.1 4.3 22.4

ATLL 2.0 1.0 25.0

nMature T and NK Lymphomas:

FFS of Different Histologies

0 1 2 3 4 5 6 7 8 9 10 11 12

AITLALCL ALK-

EATCLNK/T-nasal type

ALCL ALK+

Savage et al. Annals of Oncology 2004; 15:1467–1475.

Baseline with CHOP/CHOP-Like: PTCL-U BCCA

OS by IPI

Thinking about solutions High-Dose therapy New (or not so new) Drugs Ways to move forward

Autologous stem cell transplantation as first-line therapy in PTCL: Results of a prospective

multicenter study

N=83 CHOP x 4-6 IF CR/PR

mobilized with DexaBEAM or ESHAP

TBI + CY-ASCT Median F/U: 33 months

PTCL 39%AITL 33%ALCL 16%Med age 46.5 (30-65)

AA-IPI L-LI 49%HI-H 51%

CR/CHOP 39%PR/CHOP 40%ASCT 66%POD 29% (22% CHOP)

Reimer, P. et al et al. JCO vol 27, Jan 2009

Overall survival

0 12 24 36 48 60

Time (months)

(n=83)

3-year OS: 48%

time (months) (n=83)

Disease-free survival

0 12 24 36 48 60

Time (months)

(n=55)

3-year DFS: 53%

time (months) (n=83)

Autologous stem cell transplantation as first-line therapy in PTCL: Survival

Reimer, P. et al et al. JCO vol 27, Jan 2009

Overall Survival(IPI: high/intermediate high vs. low/intermediate low)

0 12 24 36 48 60

Time (months)

IPI: high/intermediate high (n=42) IPI: low /intermediate low (n=41)

p= 0,1799

Overall survivalIPI: high / interm.high vs. low /

interm.low

time (months)

high / interm.high (n= 42) low / interm.low (n= 41)

Overall Survival(Transplanted vs. non-transplanted)

0 12 24 36 48 60

Time (months)

non-transplanted (n=28) transplanted (n=55)

p< 0.001

Overall survivalTransplanted vs. non-transplanted

time (months)

transplanted (n= 55) non-transplanted (n= 28)

estimated 3-year OS: 71% vs. 11%

Autologous stem cell transplantation as first-line therapy in PTCL: Survival

CR vs PR p=0.22PFS 36%-no plateau

Reimer, P. et al. J Clin Oncol; 27:106-113 2009

Months0 12 24 4836

CIBMTR Auto and Allo for PTCL: Outcomes excluding patients in CR1PFS OS NRM

Auto (N = 75)

Allo (N = 108)

Auto (N = 75)

Allo (N = 108)

Auto (N = 75)

Allo (N = 108)

P <0.0001

Smith et al, ASH 2010 abstract 689

ICE and Planned ASCT for Relapsed/Refractory T-cell Lymphoma: PFS from ICE

ALL, N=40Rel, N=22

Ref, N=18

Horwitz et al, ASH 2005

Response to ICE 70% (28/40)

Received ASCT 68% (27/40)

0 12 24 36 48 60 72 84 96 108 120 132

PFS ICE months

Progress Free Survival

0 12 24 36 48 60 72 84 96 108 120 132

PFS ICE months

PFS: Relapsed versus Refractory

Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008

-Response to DLI 2/2

Retrospective Analysis of 77 PTCL Patients Who Underwent Allogeneic Stem-cell Transplantation

5 year EFS 53%

5 year OS 57%

AITL (n=11) 80%

PTCL (n=27) 63%

ALCL (n=27) 55%

Other (n=12) 33%

Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008

Retrospective Analysis of PTCL Patients Who Underwent Allogeneic Stem-cell Transplantation

Societe´ Francaise De Greffe De Moelle Et De Therapie Cellulaire

REL/REFRHistologies-ALCL-27-PTCL-NOS-27-AITL-11-NK/T-cell-5 -HSTCL-3-T-LGL-1-EATCL-1-HTLV– 2

myeloablative conditioning regimen-57

5 year TRM 34%

Thinking about solutions High-Dose therapy New (and not so new) Drugs Ways to move forward

Alemtuzumab- anti-CD52 antibody N=14, Rel/Refr-Phase II, standard dosing (30 mg iv 3x/week)1

10 PTCL, nos, RR 36% (3CR/2PR) 5 deaths-closed early (TB, zoster, aspergillus)

N=10, Phase II -10 mg x 12 doses (4 weeks) 2

PTCL nos 6, CTCL 4 Response 50% in PTCL, CR2/PR1 Less toxic

Denileukin diftitox-fusion protein-IL2-diphtheria toxin N=27, (PTCL 19) Phase II, standard dosing3

48%RR , not myelosuppressive

Is there an “R-CHOP” for TCL?

1. Enblad et al. Blood. 2004;103:2920-2924.2. Zinzani et al Haematologica. 2005;90:702-703. 3. Dang et al British Journ Haematol 136:439-447, 2007

Alemtuzumab and CHOP chemotherapy as first-line treatment of PTCL: results of a GITIL prospective

multicenter trial

2 year FFS 48%

2 year OS 53%

Gallamini et al, Blood 110:2316-2323; 2007

A-30 mg + CHOP Q 4 weeks x 8N=24 (PTCL/AITL 20)

IPI 0-1 33%2-3 58%4-5 8%

CR ALL 70.8%PTCL 50%AITL 100%

Issues with Alemtuzumab + CHOP

Toxicity– Gallamini et al– Grade 4 Infection-17%– Sepsis, Aspergillosis, JC virus, PCP

– Kim et al– Toxicity-Grade 3-4

• Neutropenia 90%, Lymphopenia 95%, Febrile neutropenia 55%• Infectious deaths 10%• Study halted early due to SAE

Heterogeneity of CD52 expression – Series of PTCL 35-40%*– Down-regulated in PTCL?– Varies by technique Flow vs Immunohistochemistry

*Piccaluga et al Haematologica 2007 92:566-567, Rodig et al. Clin Cancer Res 2006;12:7174

Foss FM, et al. ASCO 2010. Abstract 8045.

Multicenter phase II study of patients with aggressive T-cell NHL Treatment: DD 18 μg/kg/d on Days 1-2, CHOP on Day 3, G-CSF or

filgrastim on Day 4 N=49 (80% PTCL/AITL/ALCL) 7 patients completed only 1 cycle of therapy

– 3 deaths after cycle 1 (2 cardiac, 1 rhabdomyolysis)– 4 discontinued due to toxicity

Efficacy– ORR overall: 68%; 57% CR– ORR (≥2 cycles): 86%; 73% CR– Median PFS 12 mos; estimated 2-year OS 60%

Denileukin Diftitox (DD) + CHOP in First-Line PTCL (CONCEPT Trial)

Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL)

Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010

•7 trials: German High-Grade Non-Hodgkin’s Lymphoma Study Group•343 patients•Most received 6-8 courses of CHOP or CHOEP (Hi-CHOEP, or MegaCHOEP)•56% ALCL, 8% AITL

Histology N 3 yr EFS 3 yr OSALCL ALK+ 78 75.8% 89.8% ALCL, ALK- 113 45.7% 62.1% PTCLU 70 41.1% 53.9%AITL 28 50.0% 67.5%

Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: Event-free survival Younger patients treated on the NHL-B1 trial

Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: Event-free survival Younger patients treated on NHL-B1/Hi-CHOEP trial

EFS ALCL, ALK+

EFS Other subtypes

Plasma membrane

Lysosome

cysteine cysteine cysteine

cysteine

PDXPDX(& Natural

Folates)

PDXFPGSATP + MgCl2

PDX(G)n

PDX FPGH+ SH

Pralatrexate

cMOAT/MRP

ATPase

PDX(G)n

Compared to MTXPDX more efficiently enters tumor cells

(RFC-1) and is more readily polyglutamylated (FPGS)

PROPEL Pivotal Trial: Pralatrexate in Relapsed/Refractory PTCL

Pralatexate 30 mg/m² IV x 6 weeks in 7 week cycles*

N=115• Single-arm• Phase II• Relapsed or refractory PTCL

Primary endpoint• Response rateSecondary endpoints• Duration of response• Overall survival• Progression-free survival

*No pre-medications were required and patients also received vitamin B12 every 8-10 weeks, and 1 mg of oral folic acid daily.

O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.

Pralatrexate in Relapsed/Refractory PTCL

Median number prior systemic therapies: 3 (range, 1-12)

Outcome Patients (N=109 evaluable)ORR 29%• CR 11%• PR 18%Median duration of response 10.1 monthsMedian PFS 3.5 monthsMedian OS 14.5 months

PROPEL: Response Analysis by Subsets

FactorNumber of Patients

Proportion of Patients ORR

Age• < 65 years• ≥ 65 years

64%36%

27%33%

Number prior systemic regimens• 1• 2• ≥ 3

232957

21%27%52%

35%24%30%

Prior transplant• Yes• No

17%83%

33%29%

Histology• PTCL-NOS• AILT• ALCL• Transformed MF• Other

591317128

54%12%16%11%7%

35%25%38%

*includes 6 MedDRA preferred terms **includes 2 MedDRA preferred terms ***includes 3 MedDRA preferred terms1- Only 5 patients had platelet count < 10,000 μL

PROPELAdverse Events ≥ Gr 3 Occurring in ≥ 3% of Patients (n=111)

Any Grade Grade 3 Grade 4Mucosal inflammation* 70% 17% 4%

Thrombocytopenia** 41% 14% 19%1

Nausea 40% 4% 0%Fatigue 36% 5% 2%Anemia** 34% 16% 2%

Neutropenia** 24% 13% 7%Dyspnea 19% 7% 0%Hypokalemia** 15% 4% 1%Abnormal LFTs* 13% 5% 0%Abdominal pain 11% 4% 0%Leukopenia** 11% 3% 4%Febrile Neutropenia 5% 5% 0%Sepsis 5% 3% 2%Hypotension 5% 3% 1%

O’Connor OA, et al JCO Jan 18 2011

Pralatrexate for CTCL: Efficacy Results

Cohort Pralatrexate Dose mg/m2

ScheduleResponse

RateResponse

Type1 30- 3/4 weeks 100% (2/2) 2 PR2 20- 3/4 weeks 67% (2/3) 2 PR3 20- 2/3 weeks 57% (4/7) 1 CR/3 PR4 15- 3/4 weeks 50% (3/6) 3 PR5 15- 2/3 weeks 0 (0/3) ---6 10- 3/4 weeks 10% (1/10) 1 CR

Overall 39% (12/31) 2 CR/10 PRDoses >15 mg/m2, 3/4 weeks 61% (11/18)

“Optimal” dose 15 mg/m2, 3/4 weeks 10/22 (45%)

Horwitz SM, Kim Y, Foss F, et al, ASH Annual Meeting., 2010;

Response by CTCL Subtype and Stage (N = 54)

CTCL Subtype (perInvestigator)

Stage Rate at OptimalDose/Sched

% (n/N)

Response Rateat ≥ 15 mg/m2

3/4 weeks% (n/N)

OverallResponse

Rate% (n/N)

MF IBIIBIII

IVAIVB

60% (3/5)67% (4/6)50% (1/2)60% (3/5)0% (0/1)

63% (5/8)67% (8/12)50% (1/2)60% (3/5)0% (0/1)

50% (5/10)53% (9/17)50% (1/2)50% (3/6)0% (0/1)

Sézary IIBIII

IVAIVB

0% (0/1)33% (1/3)33% (1/3)0% (0/1)

0% (0/1)25% (1/4)33% (1/3)50% (1/2)

0% (0/1)25% (1/4)13% (1/8)50% (1/2)

PC-ALCL IIB ------- 100% (1/1) 100% (1/1)

All patients 45% (13/29) 51% (21/41) 41% (22/54)

Horwitz SM, Kim Y, Foss F, et al, ASH Annual Meeting., 2010;

Romidepsin in PTCL

A pan-histone deacetylase (HDAC) inhibitor FDA-approved in 2009 for use in patients with CTCL

who have received ≥ 1 prior systemic therapy Pivotal trial in PTCL presented at ASH 2010

Pivotal Trial of Romidepsin in Relapsed/Refractory PTCL

Median age: 61 years (range, 20-83) Median of 2 prior regimens (range, 1-6) 62% refractory to frontline therapy

Romidepsin 14 mg/m2 IV on Days 1,8,15 every 28 days

N=131• Single-arm• Phase II• PCTL failing ≥1 prior systemic therapy

• Systemic disease

Primary endpoint• CR rate by independent review

Secondary endpoints• CR rate by investigator assessment

• ORR• Duration of response• Time to first response• Time to progression• Safety, tolerability

T-cell lymphoma subtypes (n):• PTCL-NOS (53)• AITL (21)• ALCL (ALK-1-neg) (16)• Other (10)

Coiffier B, et al. ASH 2010. Abstract 114.

Romidepsin in Relapsed/Refractory PTCL

ORR (by IRC): 26% (34/130) CR: 13% Median duration of response: 12 months Median duration of CR: not reached (<1 to 26.3+

months) Median time to progression: 6 months Safety profile consistent with CTCL studies

– Most common grade ≥3 AEs: thrombocytopenia (24%); neutropenia (20%)

Coiffier B, et al. ASH 2010. Abstract 114.

Events with a missing toxicity grade are included.

At least one TEAE

Nausea

Fatigue

Vomiting

Thrombocytopenia

Diarrhea

Pyrexia

Neutropenia

Constipation

Anorexia

Anemia

Dysgeusia

Overall

≥ Grade 3

Infection

Treatment-Related Adverse Events in ≥ 20% of Patients (N = 131)

Hematologic Toxicities ≥ 5% (N = 131)

All Grade ≥ 3 Drug-Related

Grade ≥ 3;Drug-

RelatedD/C

Thrombocytopenia* 38% 24% 37% 23% 2%

Neutropenia† 30% 20% 29% 18% 1%

Anemia 24% 10% 20% 5% 0

Leukopenia 12% 6% 12% 6% 1%

*9 patients (7%) had a bleeding event [3 pts ≥ Grade 3]. 6/9 related to thrombocytopenia† Febrile neutropenia reported as AE in 5 patients (4%). Growth factors used in 13% of patients

D/C, events leading to discontinuation.

Brentuximab Vedotin (SGN-35) in ALCL

3 components:– Chimeric antibody SGN-30– Synthetic analog (MMAE) of the

antitubulin agent dolastatin 10– Stable drug linker

Proposed mechanism of action– Binds to CD30– Internalized into the tumor cell– MMAE is released – Tumor cell undergoes G2/M

phase cell cycle arrest and apoptosis

Preclinical activity observed both in vitro and in vivo

Reproduced with permission from Seattle Genetics, Inc.; Pro. 2009 ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology. 2009;486; Younes. EHA. 2009 (abstr 0503).

ADC=antibody-drug conjugate; MMAE= monomethylauristatin E.

G2/M cell cycle arrest and apoptosis

Brentuximab Vedotin in Relapsed/ Refractory Systemic ALCL

Median age: 52 years (range, 14-76) Median of 2 prior regimens (range, 1-6) 62% refractory to frontline therapy

Brentuximab vedotin 1.8 mg/kg IV every 21 days

N=58• Single-arm• Phase II• Relapsed or refractory systemic ALCL

Primary endpoint• ORR by independent review

Secondary endpoints• CR rate• Duration of response• PFS • OS

Shustov AR, et al. ASH 2010. Abstract 961.

Brentuximab Vedotin: Key Response Results

N=58 IRF Investigator

Overall response rate (95% CI) 86% (75, 94) 81% (69, 90)Complete remission 53% 59% Partial remission 33% 22%

Stable disease 3% 9%Progressive disease 5% 3%Histologically ineligible 3% 3%Not evaluable 2% 3%OutcomesMedian duration of OR (95% CI) Not reached (36, −) 36 weeks (31, −)Median duration of CR (95% CI) Not reached (36, −) Not reached (35, −)Median PFS (95% CI) Not reached 41 weeks (23, −)Median OS Not reached

Common Adverse Events*

Preferred Term All GradesNausea 38%

Peripheral sensory neuropathy 38%

Fatigue 34%

Pyrexia 33%

Diarrhea 29%

Neutropenia 21%

Rash 21%* Events of any relationship occurring in ≥20% of patients, N=58

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

ALCL, ALK+

Vose, Weisenburger, et al, International T-cell Classification Project

Primary Cutaneous ALCL

ALCL, ALK-

PTCL-NOS

PTCL, if CD30+ in > 80% of cells-worse prognosisHTLV-1/ATLL may be CD30+MF with large cell transformation will be CD30+

Transformed MF

Bendamustine in T-cell lymphoma (BENTLY Trial)

T-cell lymphoma subtypes (n): AILT (24) PTCL-NOS (17) ALCL (4) EATL (1) MF (1)

Bendamustine 120 mg/m2 IV on Days 1,2 every 3 weeks for 3 cycles

N=60• Multicenter, single-arm, phase II study

• Relapsed or refractory T-cell lymphoma

• ≤ 3 prior lines chemotherapy Primary endpoint

• ORR (IWC 1999 criteria)

Secondary endpoints• Safety, tolerability• Duration of response• PFS • OS

If no PD:Additional 3 cycles bendamustine

Damaj G, et al. 11th ICML; Lugano 2011. Abstract 126.

Bendamustine in Relapsed/ Refractory T-cell Lymphoma

ORR: 42%; CR: 23% Median DOR: 5.5 months

– Median duration of CR: 11.9 months

Most common grade 3/4 adverse events:– Neutropenia (49%)– Thrombocytopenia (36%)– Infections (34%)

Damaj G, et al. 11th ICML; Lugano 2011. Abstract 126.

Phase II Trial: Lenalidomide in Relapsed/Refractory TCL

Dueck G, et al. Cancer. 2010;116:4541-4548.

MF=mycosis fungoides.

Lenalidomide 25 mg PO QD on days 1-21 of each 28-day cycleUntil disease progression, death, or unacceptable toxicity

N=24• T-cell lymphoma (other than MF)

• WHO PS ≤3• Previously treated or untreated but not suitable for standard therapy

Primary endpoint• ORRSecondary endpoints• PFS• OS• Safety

Lenalidomide in Relapsed/Refractory TCL

ORR=30% (7/23) Median PFS = 96 days Median OS = 241 days (range, 8-696+ days) Common AEs

– Grade 4: thrombocytopenia (33%)– Grade 3: neutropenia (20.8%), febrile neutropenia (16.7%), pain NOS (16.7%)

Histology No. CR PR ORR, %ALCL 5 0 2 40AITL 7 0 2 29EATCL 1 0 0 0HSTCL 1 0 0 0PTCL 9 0 3 33

Dueck G, et al. Cancer. 2010;116:4541-4548.

Phase II Study of SMILE Chemotherapy in Extranodal NK/T-cell Lymphoma, Nasal Type

• SMILE = Steroid (dexamethasone), Methotrexate, Ifosfamide, L-asparaginase, Etoposide

• Patients with newly diagnosed stage IV or relapsed/refractory ENKL (N=39)

ORR 74%; CR 38% Highly myelosuppressive:– Grade 3/4 neutropenia: 8%/92%– Grade 3/4 leukopenia: 28%/72%– Grade 3/4 infection: 41%/13%– Lymphocyte count ≥ 500/mm3 added to eligibility criteria after first 2 patients

died from infection

Yamaguchi M, et al. ASCO 2010. Abstract 8044.

Can we move new therapies upfront to change standard treatment paradigms?

New Drug New Drug New Drug Etc.

Combination Alternating or Maintenance

CHOP SGN-35 or similar

•Incorporating new therapies•Adding to existing regimens may be limited (very active single agent)•Otherwise novel approaches

•Novel ways to incorporate new drugs-can be done now•Completely novel regimens-will take time

A Multi-center, Randomized, Phase 3 Study of Sequential Pralatrexate Versus Observation in Patients PTCL Who Have Not Progressed Following Initial Treatment with CHOP-based

Chemotherapy

PTCL-see eligibilityNo prior therapy (1 cycle CHOP-like allowed)Appropriate for CHOP based treatment

RANDOMIZE

Pralatrexate Maintenance

RESTAGING

observation

PD not eligible

CR, PR

“CHOP” x 6 cycles

At progression-treat as physician

discretion, including PDX

Co-Primary Endpoint OS/PFS

managing t-cell lymphoma

ash annual

phase ii study

high interm

cell lymphoma

anaplastic

phase 3 study

year os

initial treatment

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