Chronic Myelogenous Leukemiaand

Acute Lymphoblastic LeukemiaDaniel J. DeAngelo, MD, PhD

Chief of the Division of LeukemiaDana-Farber Cancer Institute

Brigham and Women’s HospitalProfessor of Medicine

Harvard Medical SchoolBoston, MA

Disclosure Information

The following relationships exist related to this presentation:• Dr. Daniel DeAngelo has served as a consultant for Amgen, Agios,

Blueprint, Incyte, Jazz, Novartis, Pfizer, Shire, and Takeda• Dr. Daniel DeAngelo has research funding from Glycomimetics, Abbvie and

Novartis

Off-Label/Investigational DiscussionIn accordance with CME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Dasatinib for Ph-like ALL; Ponatinib for untreated Ph+ ALL, rituximab for untreated ALL

CML: Management in the Era of Multiple Tyrosine Kinase Inhibitors

How do we Decide on Front-line CML Therapy

• 66-year-old man with a history of hypertension and congestive heart failure presents with a 4-month history of weight loss and night sweats.

• On exam he has decreased breath sounds at lung bases with 1+ pedal edema.

• A discussion ensues regarding benefits and risks with commencing first versus second generation tyrosine kinase inhibitor (TKI)

WBC 80 x 109/L Left shift with 1% blastsHgb 9 g/dL 80% BCR-ABL1 by FISHPlatelets 100 x109/L

Maslak, P. ASH Image Bank; Image ID: 2456 Maslak, P. ASH Image Bank; Image ID: 1474

Life Expectancy of Patients with CML Approaches the General Population

Bower et al., J Clin Oncol 2016 34: 2851-7.

CML Current Status: 2019

ImatinibNilotinibDasatinib

Ponatinib

Refractory responseSuboptimal responseRelapseIntolerance

SCT

NilotinibDasatinibBosutinib

Refractory responseSuboptimal responseRelapseIntoleranceT315I

Other: Omacetaxine

Where does Generic imatinib fit in?

What Can We Expect FromFront-line Imatinib in CP CML?

IRIS Trial Data

MMRCCyR

BJ Druker et al. New Engl J Med 2006;355:2408-17.

MMR

A Hochhaus, RA Larson, F Guilhot, et al. New Engl J Med 2017 376: 917-27.

Role of Second-Generation TKIs in First-line Treatment of CML-CP

• There are consistent data from multiple studies demonstrating that patients who have very rapid responses with any TKI have excellent long term outcomes and that some patients with slower responses fare more poorly.

• Responses are faster with “second” generation TKIs

BUT….

• NO SURVIVAL ADVANTAGE with nilotinib, dasatinib or bosutinib in randomized trials

• Only about 60-65% of patients remain on their initial drug

• And then there are the toxicities…

ENESTnd: Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML

• Primary endpoint: MMR at 12 mos, defined as ≤ 0.1% BCR-ABL(/ABL ratio) on International Scale

• Secondary endpoint: CCyR by 12 mos

• Other endpoints: time/duration of MMR and CCyR; EFS, PFS, time to AP/BP, OS

• Stratification by Sokal risk

Imatinib 400 QD (n = 283)

Nilotinib 300 BID (n = 282)

RANDOMIZE

Nilotinib 400 BID (n = 281)

Newly Diagnosed CML-CP

(N = 846)217 centers;35 countries

Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.

Dasatinib vs Imatinib in Treatment-naive CML: DASISION

• Primary endpoint: Confirmed CCyR by 12 months

• Secondary/other endpoints: Rates of CCyRand MMR; times to confirmed CCyR, CCyRand MMR; time in confirmed CCyR and CCyR; PFS; overall survival

Randomized*

Imatinib 400 mg QD (n = 260)

Dasatinib 100 mg QD (n = 259)N = 519

108 centers

26 countries

*Stratified by Hasford risk score

Kantarjian H, et al. N Engl J Med. 2010;362(24):2260-2270.

SPIRIT 2

O’Brien et al. ASH 2018

LONGER TERM FOLLOW-UP OF SECOND and THIRD GENERATION TKIs

• Dasatinib - late pleural effusions, pulmonary hypertension; T/NK cells

• Nilotinib – hyperglycemia, peripheral arterial occlusive disease, other arterial thromboses

• Bosutinib – less information; diarrhea and transaminitis

• Ponatinib - MAJOR arterial thrombotic issues

Algorithm for Frontline TKI Therapy in CML

Neil P. Shah; JCO 2018, 36, 220-224

Bosutinib offers a third 2nd Gen choice anda fourth upfront choice

CML Monitoring Frequency

NCCN Guidelines 2019; Mahon et al., Lancet Oncol 2010; 11: 1029–35

The 3 month QRT-PCR may be uniquely important in defining long term outcome!If these criteria aren’t met (primary resistance, ~15% on imatinib):check for ABL TKD mutation and switch therapy

Repeat marrow exams are not necessary once CCyR achieved (check at 6 months and 6 months thereafter prn) (PB FISH also reasonable)

Check QPCR q 3 months x 3yrs, then q 3-6 months thereafter or if increase by 1 log after MMR achieved, then repeat in 1-3 months

When to check for ABL TKD mutation and switch therapy:

loss of response (heme or cytog relapse) or disease progression to AP/BP

confirmed 1 log increase in bcr-abl1 transcript and loss of MMR

CML Molecular Response Milestones

BCR-ABL1 (IS) 3 months 6 months 12 months > 12 months

> 10% YELLOW RED

1% - 10% GREEN YELLOW RED

0.1% - 1% GREEN YELLOW

< 0.1% GREEN

Clinical Considerations Treatment options

RED Evaluate compliance and drug interactionsMutation testing

Switch to alternate TKIConsider screen for HSCT

YELLOW Same as above Consider switch to alternate TKI or continue (may increase dose of imatinib to 800 mg)

GREEN Monitor response and toxicity Continue same TKI

NCCN 2019 Guidelines

ABL Kinase Inhibitor Resistance

Resistance Due to BCR-ABL1 Point Mutations

Relatively resistantCompletely resistant

Single BCR-ABL1 Mutants

Imatinib

NilotinibBosutinibDasatinib

Ponatinib

TKI Resistance

T315I

O’Hare et al. Cancer Cell 2009.

1. Line therapy

ImatinibDasatinib

Nilotinib

Dasatinib

Nilotinib

Bosutinib

Ponatinib

2. Line therapy 3. Line therapy

Dasatinib

Nilotinib

Ponatinib

Bosutinib

Omacetaxine

T315I

70%

Treatment History and Salvage Therapy:Likelihood of CCyR

Bosutinib

1. Line therapy

ImatinibDasatinib

Nilotinib

Dasatinib

Nilotinib

Bosutinib

Ponatinib

2. Line therapy 3. Line therapy

Dasatinib

Nilotinib

Ponatinib

Bosutinib

Omacetaxine

20%

20%

50-70%

10%

Treatment History and Salvage Therapy:Likelihood of CCyR

Bosutinib

Ponatinib After Failure of Second Generation TKI

Cortes JE et al. Blood 2018

Incidence of AOE and VTE

Cortes JE et al. Blood 2018

• Start ponatinib at 30 mg/day• Reduce to 15 mg after MMR

ABCDE Steps to Reduce CV Risk in Patients with CML

• A• Awareness of CV risks and signs• Aspirin in appropriate patients• Ankle-brachial Index (ABI) at baseline and f/u

• B• Blood pressure control

• C• Cigarette/tobacco cessation• Cholesterol monitoring and treatment

• D• Diabetes mellitus monitoring and treatment• Diet and weight control

• E• Exercise

Moslehi and Deininger, J Clin. Oncol 2015 33: 4210-8

Biochemistry• Caliper ABL1 assay IC50 – 0.4nM

Biophysics• ITC ABL1 assay IC50 – 0.7nM

Selectivity• Kinase selectivity restricted to ABL1 and ABL2

Cardio-safety profile• hERG assay >30uM

• No evidence of QT prolongation in dog jacketed telemetry up to 600mg/kg

Asciminib (ABL001) a potent and selective inhibitor of ABL

Nilotinib(ATP site)

ABL001 (myristoyl site)

Wylie et al., ASH 2014, Abstract #398

Asciminib in patients with a T315I Mutation

Rea et al ASH 2018

TKIDiscontinuation

Studies

POTENTIAL BENEFITS OF STOPPING TKIs

• It’s better not to take medications you don’t need• Pregnancy (can use IFN if rsposne needed)• Reduction or elimination of TKI toxicities

• Low grade, chronic side effects• More severe side effects which haven’t happened

yet (particularly cardiovascular)• The allure of the concept of “cure”

• COST

Duration of Therapy: Is TKI Therapy Forever?• Stop Imatinib Trial (STIM)

• On imat x >3 y with sustained CMR for > 2 y• RFS after discontinuation of imatinib, N=100

• 6-mo: 45%, 12 mo: 43%, 24 mo: 41%

The LAST Study

100

80

60

40

20

0

Surv

ival

With

out M

olec

ular

R

elap

se

Pts at Risk, n 100 57 36 28 27 23 20 16 6

Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035

Chronic Myeloid Leukemia: Conclusions

• Chronic Myeloid Leukemia• First line imatinib vs nilotinib vs dasatinib vs bosutinib?

• How to choose? Imatinib a very reasonable choice for elderly and low-risk patients• Late side effects important (CV for nilotinib; pleural effusions for dasatinib)• Compliance still most important

• Ponatinib• T315I• Third line therapy (US)

• Need to minimize CV risk factors• New Agents and ideas

• Asciminib (ABL001) in R/R CML • Combination therapy

• TKI Discontinuation only in appropriate patients with good follow up

Current Approaches in the Management of

Acute Lymphoblastic Leukemia

Case Presentation• 21-year-old woman with 2-week history of fatigue, dizziness and

bleeding after dental procedure.• WBC: 85 x 109/L; Hgb: 10.3 g/dL; Platelet count: 17 x 109/L; differential showed 92%

blasts• Immunophenotyping showed positivity for CD10, CD19, HLA-DR, TdT (precursor B-

cell, common ALL). Negative for CD20, Ig, and myeloid antigens.• Cytogenetics: 46 XX, der19 t(1;19).

• E2A-PBX1 fusion.

• PCR negative for BCR-ABL

• How would you treat this patient?

Adult ALL - Prognosis

• Age: Adult outcomes are inferior to pediatric outcomes• Genetics: Alterations impact prognosis

• Philadelphia-chromosome [t(9;22)]• MLL translocation [t(v11q23)]• Complex karyotype• Low hypodiploid (now known to be associated with TP53

mutation)• “Ph-like” gene expression profile• Molecular mutations (IKZF1, TP53)

• Flow: Early T-cell phenotype (ETP-ALL)Westbrook et al. Blood 1992; 82: 2983Wetzler et al. Blood 1999; 93: 3983

Mullighan et al. N Engl J Med 2009; 260: 470Moorman et al. Blood 2010; 115: 206

Safavi et al. Blood. 2017; 129: 420

Incidence of Some Important Cytogenetic-Molecular Abnormalities in ALL

Ph 2-5%

Hyperdiploid >50

28%

TEL-AML

25%

Ph 25%

Hyperdiploid >505%

TEL-AML 2%

Pediatric Adult

Pui. NEJM. 2004;350:1535-1548.

Background: Ph+ Disease

• About 1/3 of ALL cases have the BCR-Abl fusion gene.

• More frequent in older adults: approximately 50% of pts > 60 years.

Iacobucci et al. J Clin Oncol 2018; 35: 975

Philadelphia Chromosome-Like ALL

• Associated with genetic alterations that activate cytokine receptor genes and kinase-signaling pathways.

• Majority over-express CRLF2. Among CRLF2 over-expressors, 85% have mutations in JAK-STAT and Ras pathways. Particularly poor prognosis!

Roberts et al. N Engl J Med 2014; 371: 1005Tran and Loh. ASH Education Book 2016Jain et al. Blood 2017; 129: 572

ETP vs. “Traditional” ALL

T-ALL

ETP

• 15% of all T-ALL in children, ~35% in adults

• Retain ability to differentiate into T-cell and myeloid lineage

• Lack CD1a, CD8, and usually CD5weak

• May express myeloid or stem markers

• Enriched for mutations in cytokine receptor and RAS signaling

• NRAS, KRAS, FLT3• IL7R, JAK1, JAK3

• DNMT3A in ~15% of cases• Lower frequency of NOTCH mutations

• ~20% of ALL• TDT+, cyCD3+

• Other markers variable based on differentiation

• Enriched for mutations in:• NOTCH1- ~60%• FBXW7- ~15%• CDK2NA

Litzow and Ferrando, Blood, 2015Marks and Rowntree, Blood, 2017Neumann et al., Blood, 2013

MRD for Remission Assessment in Ph-Negative Adult ALL (SR-ALL in Adults: GMALL 06/99)

Brüggemann M et al. Blood. 2006;107:1116-1123.

Identification of patients with rapid tumor clearance and excellent prognosis Identification of patients with persistence of MRDand poor prognosis

Acute Lymphoblastic Leukemia

Ph-positive Ph-negative

AYA (18-39) Adult (40-60) Older Adult (>60)

Pediatric-inspired Adult Regimens Low Intensity

Add TKI

AYA - Definition

Group Age GroupDFCI 18-50Spanish 15-30French 15-60CALGB 10403 18-40SWOG 805 18-50

DeAngelo et al, Leukemia 29:526, 2015Ribera et al, JCO 26:1843, 2008Huguet et al, JCO 27:911, 2009

AYA definition is relatively loose

Event-Free Survival: CALGB (adult group) vs CCG (pediatric group)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12 14

CCG (n=197)

CALGB (n=124)

Stock, W. et al. Blood 2008;112:1646-1654

Log Rank p<.0001

Ages 16-20

Stock et al. Blood 2019; 133: 1548-59

DFCI Adult Consortium Trial (01-175): OS and DFS

4-yr = 69%Median f/u = 4.5 yrs

DeAngelo et al., Leukemia 2015

Disease-free SurvivalOverall Survival

4-yr = 67%Median f/u = 4.5 yrs

Adult Patients with ALL

Asparaginase Regimens: CALGB 8811• Phase II Multicenter trial• 197 pts with untreated ALL, aged 16-80

• Induction: Cyclophosphamide, Daunorubicin, Vincristine, Prednisone, and L-asparaginase

• Early intensification• CNS ppx with interim maintenance• Late intensification• Prolonged maintenance

• 85% CR• 46% remained

in continuous CR at 3 years• L-asparaginase is well

tolerated in adults

Larson et al. (1995) Blood 85: 2025-2037

Hyper-CVAD

CVAD Maintenance

Until 2 years from Dx

ARA-C/MTX

• CVAD = Cytoxan, vincristine, doxorubicin, dexamethasone

• ARA-C/MTX• CNS prophylaxis with IT-MTX• POMP Maintenance until 2 years from

diagnosis

H Kantarjian et al., JCO 2000

Repeat sequence X 4 cycles

Thomas et al., JCO 2010

Rituximab Improves Outcome in CD20 Positive Patients

Ph+ ALL

Chalandon Y, et al. Blood 2015;125:3711

IM (800mg for 28d) IM (800mg for 14d)

HD-MTX + HD-AraC+ IM (800mg x 14d)

MRD1

MRD2

6-MP + MTX + IM (600mg x 14d)

PBSC collection if Auto-SCT

Allo-SCT / Auto-SCT

Chemotherapy Dose Intensity during InductionGRAAPH 2005 Trial (n=270)

Median follow-up, 4.8 years

Steroidprephase

R

IM -deintens.

IM -HyperCVAD

InterphaseTwo cycles

Cycle 1First induction

Cycle 2Consolidation / 2nd induction

CREarly Death

88.7%6.7%

97 %0.7%

GRAAPH 2005: Outcome is Independent of Chemotherapy Intensity during Induction

Chalandon Y, et al. Blood 2015;125:3711–9

OVERALL

• Median EFS and OS were 2.1 years (1.48–2.67) and 3.6 years (2.55–NR)

• At 5 years, EFS was estimated at 37.1% (95% CI, 31.1–43.1)

• At 5 years, OS was estimated at 45.6% (95% CI, 39.2–51.8).

EFS OS

Arm A

Arm B

Arm A

Arm BIntensive Intensive

deintensified deintensified

GRAAPH 2005 trial: Role of allogeneic SCT

Chalandon Y, et al. Blood 2015;125:3711–9

• Time-dependent analysis; Simon-Makuch plots; t0, CR achievement• HR, 0.69 [95% CI, 0.49–0.98]; P=0.036 by the Andersen-Gill test

no alloSCT in CR1

Allo SCT in CR1

GRAAPH 2005 study schema Relapse free survival

Farhad Ravandi et al. Blood Adv 2016;1:250-259

US intergroup study of chemotherapy plus dasatiniband allogeneic SCT in Ph+ ALL (n=94)

Age: 44y (20-60)

Farhad Ravandi et al. Blood Adv 2016;1:250-259

US intergroup study of chemotherapy plus dasatiniband allogeneic SCT in Ph+ ALL (n=94)

Overall survival with and without censoring for alloSCT

Ponatinib combined with Hyper-CVAD in Front- Line Therapy of Patients with Ph+ ALL (n=37)

Jabbour E, Lancet Oncology, 16 (15), 2015, 1547–1555

Relapsed/Refractory Patients with ALL

• Blinatumomab is a BiTE antibody designed to direct cytotoxic T-cells to CD19-expressing cancer cells1, and is approved for use in R/R Ph− B-ALL2

1. Figure adapted from Nagorsen D and Baeuerle P. Exp Cell Res 2011;317:1255–1260; 2. Blinatumomab summary of product characteristics 2016

Blinatumomab

α-CD19antibody

α-CD3antibody

VL

VH

VL

Target antigenCD19

CD3

Redirected lysis: T-cell-mediated

cytotoxicity

T-cell

NHL/ALL cell

Blinatumomab(BiTE®)

VH

FLAG, fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor; HiDAC, high-dose cytarabineThe induction phase consisted of two cycles of assigned protocol-specified therapy. The consolidation phase consisted of three cycles of assigned protocol-specified therapy in subjects who achieved a bone marrow response at the end of the induction phase*Dexamethasone was given pre-dose to prevent cytokine-release syndromeExtracted from Kantarjian HM et al. N Engl J Med 2017;376:836–847

TOWER: Phase III Study of Blinatumomab versusSOC Chemotherapy in R/R ALL

• Primary endpoint: OS

• Key secondary endpoints: CR in induction; CR/CRh/CRi in induction; EFS

• Other secondary endpoints: duration of CR, MRD remission, rate of allo-HSCT, incidence of AEs

Patients ≥18 years with R/R Ph- pre-B-ALL:• Refractory to intensive combination

chemotherapy (initial or salvage)• Untreated first relapse (remission <12 months)• Untreated second or greater relapse• Relapse at any time after allo-HSCT

2:1 randomisation(N=405)

Blinatumomab* (n=271)

• Continuous infusion; 4 weeks on, 2 weeks off; 9 µg/day for 7 days, then 28 µg/day (Weeks 2–4)

SOC chemotherapy (n=134)

Investigator choice:• FLAG ± anthracycline; HiDAC-based;

high-dose MTX-based; or clofarabine-based

• Continuous infusion; 4 weeks on, 8 weeks off; 28 µg/day

Stratified by age, prior salvage and prior

allo-HSCT

Kantarjian HM et al. N Engl J Med 2017;376:836–847

TOWER: Treatment Response and Molecular Remission Among Responders

0%

10%

20%

30%

40%

50%

60%

Blinatumomab (N=271)

44%

25%

34%

16%

(P<0.001)

(P<0.001)

Overall response(CR/CRh/CRi)

Complete remission(CR)

Prop

ortio

n of

pat

ient

s (w

ith u

pper

95%

Cl)

SOC (N=134) • 76% of responders with blinatumomab and 48% with SOC achieved MRD negativity

• Median OS 7.7 vs 4.0 mos (P=0.01)

Advani A et al. J Clin Oncol 2010;28:2085–2093; DeAngelo DJ. https://www.hemedicus.com/pdf/fss_slides/04_DeAngelo.pdf [accessed 6 March 2018);

de Vries JF et al. Leukemia 2012;26:255–264

Inotuzumab Ozogamicin

N-acetyl γ calicheamicinAverage loading of calicheamicin derivative on mAb is

5–6 moles of calicheamicin/mole of mAb (range 3–9) for InO; ~100% of mAbs conjugated2,3

4-(4’-acetylphenoxy) butanoic acid linker1 MoA retains activity against tumour cells with slow cycling times2,3

Intact ADC

HumanisedIgG4 anti-CD22

FLAG, fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor; HiDAC, high-dose cytarabine*CR/CRi based on first 218 patients randomised; †OS assessed in all patients after ≥248 eventsExtracted from Kantarjian HM et al. N Engl J Med 2016;375:740–753

INO-VATE: Phase III Study of Inotuzumab versus SOC in R/R ALL

• Two primary endpoints: CR/CRi* and OS†

• Key secondary endpoints: PFS, remission duration, stem cell transplant rate, safety and MRD rate among responders

• Patients ≥18 years with R/R CD22+ ALL

• Due for Salvage 1 or 2 therapy

• Ph- or Ph+

1:1 randomisation(N=326)

InO (n=164)

• Starting dose: 1.8 mg/m2/cycle• 0.8 mg/m2 on Day 1; 0.5 mg/m2

on Days 8 and 15 of a 21–28 day cycle (≤6 cycles)

SOC (n=162)

• FLAG (≤4 cycles) or

• Ara-C plus mitoxantrone (≤4 cycles) or

• HiDAC (≤12 doses)

Stratifications:• Duration of first

remission ≥12 versus <12 months

• Salvage 1 versus 2• Age <55 versus

≥55 years

CR/CRi MRD negativity in responders

INO-VATE: Treatment Response and Molecular Remission Among Responders

InO SOC

78.4%(69/88)

28.1% (9/32)

50.3% difference

P<0.001

0

10

20

30

40

50

60

70

80

90

InO SOC

CR/C

Ri (%

)

80.7%

29.4%

51.4% difference

P<0.001

88/109

32/109

In both arms, most patients achieved

CR/CRi in Cycle 1 (InO, 73%;

SOC, 91%)

28.1% (9/32)

Kantarjian HM et al. N Engl J Med 2016;375:740–753

• Median OS 7.7 vs 6.8 mos (P=0.04)• 2-year survival rate:

InO 23% (95% CI 16–30) vs SOC 10% (95% CI 5–16)

Novartis – ELIANA• Tisagenlecleucel (Kymriah)• N=75* (16 patients did not get their

infusion)• Pediatric/young adult B-ALL (26 yrs)• MRD negative CR rate 81%• EFS:

• 6 month – 73%• 12 month – 50%

• OS:• 6 month – 90%• 12 month – 76%

Maude SL et al NEJM 2018;378:439

Anti-CD19 CAR T-cell Pharmaceutical Trials: B-ALLJuno - ROCKET• N=38 (32 morphologic; 6 MRD+)• Adult B-ALL• JCAR015 (co-stimulatory domain

CD28)• CR rate

– Morphologic: 59%

• Overall Survival:– All patients: median OS 8.1 mos

(95%CI; 5.2-NR)– Morphologic: median OS 6.1 mos

(95%CI; 5.2-NR)

• Study halted due to 5 cases of fatal NTX

DeAngelo DJ, et al. SITC 2017:p217

Acute Lymphoblastic Leukemia: Conclusions

• Pediatric regimens for AYA patients• What is the upper age limit?

• MRD must be assessed in all patients with ALL.• Blinatumomab now approved for MRD positive ALL

• Lower intensity therapy seems appropriate for older adults with Ph+ ALL

• Is transplant still necessary for patients who are in molecular remission?• Unclear what is the best approach for Ph-like and ETP ALL

• MRD based treatment algorithm?• Both blinatumomab and Inotuzumab are superior over SOC for

patients with R/R ALL• Where will CAR T-cells fit in?

AcknowledgementsDFCI Clinical Leukemia TeamRichard Stone Andy LaneDavid Steensma Tony LetaiMartha Wadleigh Coleman LindsleyJacqueline GarciaMarlise LuskinEric WinerGoyo Abel

Ilene Galinsky, NPSiobhan Creedon, NPKat Edmonds, NPAdriana Penicaud, PAMary Gerard, PAEllen Toomey-Mathews, RN

The End

Questions ?Email: daniel_deangelo@dfci.harvard.eduPhone: 617-632-2645Administrative Assistant: 617-582-8410New Patients: 617-632-6028Page: 617-632-3352 #41284