Graft-vs.-Host Disease and Umbilical Cord

Transplantation Amin M. Alousi, MD

Associate Professor of Medicine Department of Stem Cell

Transplantation

GVHD Disclosures: Therakos, research funding; All therapeutics are off-

label.

Umbilical Cord Transplantation and GVHD and

Donald Rumsfield . . .

“ There are known knowns; there are things we know that we know. There are known unknowns; that is

to say, there are things that we now know we don't know.

But there are also unknown unknowns – there are things we do

not know we don’t know ”

—former United States Secretary of Defense, Donald Rumsfeld

What we know

What we do not know

What we do not know to know that we may

never know

Umbilical Cord Transplantation and GVHD . . .

Things claimed to be known That is things claimed to be a fact

Which are in fact, wrong

Umbilical Cord Transplantation and GVHD and Weapons of Mass Destruction . . .

Umbilical Cord Blood Transplants: Background

Unrelated Umbilical Cord transplantation has expanded the donor pool for patients who do not have an HLA-matched sibling or unrelated donor.

This is primarily due to the fact that HLA mismatches are more “permissible” resulting in rates of GVHD comparable to matched unrelated donors.

However, outcomes have been hampered by increased treatment-related mortality.

vs. MUD Peripheral Blood Less Acute and Chronic Hazard Ratio p value

Acute GVHD 0·57 0·002 Chronic GVHD 0·38 0·001

vs. MUD Bone Marrow Less Chronic Hazard Ratio p value

Acute GVHD 0·78 0·13 Chronic GVHD 0·63 0·01

vs. 1-ag MM PB or BM Less Acute and Chronic Acute GVHD Hazard Ratio p value vs. 7/8 Bone Marrow 0·59 0·01 vs. 7/8 Peripheral Blood 0·57 0·002 Chronic GVHD vs. 7/8 Bone Marrow 0·59 0·01 vs. 7/8 Peripheral Blood 0·49 0·002

Eapen et al. Lancet Oncol. 2010

Single Unit 4-6/ 6 Matched Cord Blood vs. Adult Unrelated Donors

TRM Hazard Ratio p value vs. MUD Bone Marrow 1·69 0·003

vs. MUD Peripheral Blood 1·62 0·003 vs. 1-antigen Mismatched BM 1·06 0·76 vs. 1-antigen Mismatched PB 0·95 (0·68–1·34) 0·78

Eapen et al. Lancet Oncol. 2010

The Paradox Less GVHD more Treatment Related Mortality (TRM)

Single Unit 4-6/ 6 Cord Blood vs. Unrelated Donor

Double Unit Umbilical Cord vs. Matched Related, Matched

Unrelated and Mismatch Unrelated Donor

Multivariable Analysis of Outcome Acute GVHD Grades II-IV Relative Risk p value

Double UCB Donor 1.0 Matched Related Donor 1.08 0·57

Matched Unrelated Donor 1.83 <0.01 Mismatch Unrelated Donor 2.35 <0.01

Less Acute than in MUD and Mismatch Unrelated Donor

Chronic GVHD Relative Risk p value Double UCB Donor 1.0

Matched Related Donor 1.58 0·03 Matched Unrelated Donor 1.71 0·01 Mismatch Unrelated Donor 2.07 0.01

Less Chronic than in MRD, MUD and Mismatch Unrelated Donor

Transplant-related mortality (TRM) Hazard Ratio p value Double UCB Donor 1.0

Matched Related Donor 0.31 <0.01 Matched Unrelated Donor 0.61 0.13 Mismatch Unrelated Donor 0.38 <0.01

But . . . Higher TRM than in MRD or MUD

Brunstein and Delaney. Blood. 2010

Risk Factors for GVHD following UCB transplantation: Selection of Cord Units

Does degree of HLA matching impact GVHD rates following umbilical cord transplantation?

Factors Associated with Acute GVHD after Cord-Blood Transplantation

Gluckman E et al. N Engl J Med 1997.. Rubinstein P et al. N Engl J Med 1998.

Risk Factors for GVHD following Single and Double Unit UCB transplantation: Selection of Cord Units

Factors associated with grade II-IV acute GVHD multiple regression analysis

HLA matching (engrafting unit)

RR of acute GVHD (95% CI) P

6/6 1.0

5/6 1.9 (0.9-4.2) .11

4/6 1.4 (0.7-3.2) .36

MacMillan et al. Blood. 2009; 113: 2410-15.

Risk Factors for GVHD following UCB transplantation: Selection of Cord Units: Impact of C-locus.

Cords historically are selected based on intermediate-resolution typing at the HLA-A and B loci and allele-level typing at DRB1.

Recently, the relative importance of matching at HLA C has been retrospectively studied.

TRM was higher in: Patients with 6/6 match unit but mismatched at HLA-C

versus those matched at C. Patients with 5/6 match unit + second mismatch at HLA-C

versus those matched at C.

However, mismatching at the C-locus (or any other loci) did not impact the rates of acute or chronic GVHD.

Eapen et al. Lancet Oncol. 2011; 12: 1214-21.

Hazard Ratio for TRM and OS associated with a single mismatch at HLA- A, B, C or DRB1

versus a match in that locus in the presence of 0, 1, 2 or 3+ mismatches at other loci.

Treatment Related Mortality Overall Survival

Eapen et al. Lancet Oncol. 2011; 12: 1214-21

Single Mismatch at locus vs. Match at that locus plus 0 or 1 other mismatches:

Higher TRM

Single Mismatch at locus vs. Match at that locus plus 0 or 1 other mismatches: Overall Survival Not Impacted

Cumulative incidence of Acute GVHD Grade III/IV: Impact of matching based on allele level typing HLA-A,-B,-DRB1 HLA-A,-B,-C,-DRB1,-DQ

Ponce et al. BBMT. 2013.

Roughly 1/3rd pts retrospectively found to be < 4/6 match

Risk Factors for GVHD following UCB transplantation: Selection of Cord Units

Does degree of HLA matching impact GVHD rates following umbilical cord transplantation?

Answer: Perhaps (when units are poorly

matched at allele level typing)

Risk Factors for GVHD following UCB transplantation: GVHD Prophylaxis Regimens

Does Using Methotrexate matter?

Is Mycophenolate Better?

Does the Dose of Mycophenolate Matter?

What about Rappamune (Sirolimus)?

Methotrexate in GVHD prophylaxis lowers the likelihood of Neutrophil recovery.

Herr A et al. Blood 2010;116:1849-1856

Hazard Ratio of 0.48 (95% CI, 0.31-0.73; p<0.001) on MV analysis

Use of Mycophenolate (MMF) in GVHD Prophylaxis

• In the Non-Cord setting, most studies have shown comparable rates of acute GVHD with CNI + MTX versus CNI + MMF.

• In the non-myeloablative adult donor setting, CNI + MMF is often employed to minimize toxicity associated with MTX.

• Similarly, because of the concern of engraftment in cords when MTX is used, most centers (at least within the U.S.) have replaced MTX with MMF.

• In the cord setting, there is limited evidence supporting this approach with no comparisons of CNI+MTX versus CNI+MMF.

Factors Single Double P Total N= 80 N=185 Conditioning < .01 Myeloablative 61 (76%) 78 (42%) Nonmyeloablative 19 (24%) 107 (58%) Use of ATG in the conditioning < .01 Yes 46 (58%) 49 (26%) No 34 (43%) 136 (74%) GVHD prophylaxis < .01 CSA/MP 46 (58%) 4 (2%) CSA/MMF 33 (41%) 181 (98%) CSA/MTX 1 (1%) 0

Factors associated with grade II-IV acute GVHD: multiple regression Factor RR of acute GVHD (95% CI) P ATG in conditioning

No 1.0

Yes 0.5 (0.3-0.9) .02 MMF as GVHD prophylaxis

No 1.0

Yes 0.5 (0.2-1.3) .14

ATG only given in those patients not getting MMF

Even with no ATG in the MMF group trend for less acute GVHD

Addition of MMF to CNI: trend for lower acute GVHD when compared to CNI + steroids

MacMillan et al. Blood. 2009. 113: 2410-15

MMF Twice Daily or Thrice Daily Dosing?

• Thrice daily versus Twice daily dosing of MMF was found to be associated with better PK’s in the setting of non-myeloablative, MUD transplants.

• Poor Donor T-cell chimerism was seen in patients with low MPA Css but no association with acute GVHD incidence.

• Based on this analysis some have recommended thrice daily dosing for prophylaxis in NMA transplants.

• Not extensively studied in the umbilical cord setting.

• MMF may cause neutropenia and in the non-transplant setting this has been shown to be dependent on drug levels.

Giaccone et al. Blood. 2005. 106: 4381.

Letter to Editor: Delayed neutrophil engraftment in cord blood transplantation with intensive administration of mycophenolate for

GVHD prophylaxis Single-Unit Cord Blood Transplant BMT

b.i.d. Dosing t.i.d. Dosing b.i.d. Dosing t.i.d. Dosing

No. of Patients 13 15 9 8

Median age, yrs 49 (21-66) 52 (20-66) 42 (32-58) 48.5 (35-59)

Sex, male/female 5/8 9/6 6/3 6/2

Diagnosis AML ALL MDS NHL Others

1 5 6 1 0

2 5 5 1 2

2 2 4 0 1

0 2 3 3 0

Conditioning Myeloablative Non-Myeloablative

9 4

6 9

8 1

5 3

Median CD34+ cells,

X 106/kg (range)

P

0.10 (0.04-0.21)

0.09 (0.03-0.19)

1.30 (0.74-2.60)

1.05 (0.23-3.70)

0.67 0.53

Neutrophil Engraftment Median period, days

P

17 (14-18) 22 (14-41) 11 (9-17)

11 (8-14)

0.016 0.696

Okamura et al. BMT.2011. 46: 148-149.

Sirolimus and Tacrolimus for GVHD prophylaxis in Double Cord Transplant following Flu-Mel-ATG

Days -8 -7 -6 -5 -4 -3 -2 -1 0

FLUDARABINE 30 mg2 / day X 6 days Mel 100

mg/m2

**ATG 1.5

mg/kg

ATG 1.5

mg/kg

ATG 1.5

mg/kg

ATG 1.5

mg/kg

INFUSE TWO CORD UNITS

Tacrolimus (level 5-10 ng/ml) Sirolimus* (level 3-12 ng/ml)

* Oral Loading Dose of 12mg then once daily to maintain level ** Moving forward, ATG dose lowered to 1.0mg/kg Cutler et al. BMT. 2011. 46: 659-67.

Patient and Graft Characteristics

N 32 patients

Age in years (range) 53 (19-67)

Weight in kg (range) 75.9 (52-113)

Diagnosis NHL AML Hodgkin Disease MDS CLL ALL CML/MPD

10 9 5 4 1 1 2

High Risk Malignancy 20 (63%)

Previous Transplantation 9

HLA Match (A, B, DR) 4/6, 4/6 4/6, 5/6 5/6, 5/6 5/6, 6/6

16 13 2 1

Umbilical Cord Blood Cell Dose Cord Unit 1, TNC/kg, median X 107 (range) Cord Unit 2, TNC/kg, median X 107 (range) Combined, TNC/kg, median X 107 (range)

2.67 (1.87-3.91) 2.33 (1.51-3.94) 5.16 (3.66-7.58)

• Day 100 Acute GVHD was 9.4% and

chronic was 12.5%. • No Deaths caused by GVHD • No Cases of TMA or VOD • 100 day and 2-yr NRM: 12.5 and 34% • This related favorably to previous

reported acute GVHD incidence rate of 40% using CSA+MMF and similar dUCBT conditioning regimen.

Cutler et al. BMT. 2011. 46: 659-67.

Neutrophil Engraftment: 21 days (13-70)

Risk Factors for GVHD following UCB transplantation: GVHD Prophylaxis Regimens

Does Using Methotrexate matter? Avoid

Is Mycophenolate Better? Probably Yes

Dose the Dose of Mycophenolate Matter? Unknown at least for Cord Transplants

What about Rappamune (Sirolimus)? Encouraging Results in Double UCT following

Flu-Mel-ATG conditioning

Risk Factors for GVHD following UCB transplantation: ATG or No ATG

Should ATG be given in UCB Transplantation?

Risk Factors for GVHD following UCB transplantation: ATG or No ATG

Use of ATG has been shown to reduce the rate of acute GVHD II-IV by 50% (RR=0.5; 0.3-0.9, p=0.02).

Limited studies suggest ATG may increase risk for infections,

specifically viral (adenovirus and EBV). Both out of concern for infections and to promote recovery of

thymopoiesis (immune reconstitution) some centers have removed ATG from conditioning.

Risk Factors for GVHD following UCB transplantation: ATG or No ATG

MSKCC has adopted removal of ATG and recently published their experience.

Engraftment was not impacted by removal of ATG.

Cumulative Incidence of Grade II-IV acute GVHD was comparable to other reports of DUCBT at 43%.

Concerning was rate of severe Grade III/IV acute GVHD with more than half cases of GVHD > Grade III (19 of 31 cases).

Sauter/ Barker. BBMT. 2011. 17: 1460-71.

• 75% of patients free from serious infections after day 120. • However, despite removal of ATG, viral infections remain and associated with GVHD:

• All EBV Infections happened within the context of GVHD/Steroids. • All Cases of Adenovirus colitis happened within the context of GVHD/steroids. • All late CMV infections occurred within the context of GVHD/steroids.

MSKCC experience with ATG-free ablative and non-ablative, Double Umbilical Cord Transplant in 72 patients

Sauter/ Barker. BBMT. 2011. 17: 1460-71.

Risk Factors for GVHD following UCB transplantation: ATG or No ATG

Should ATG be given in UCB Transplantation?

Inconclusive evidence, removal seems to result in higher GVHD (especially grades III/IV) and this may negate the

desired benefit (protection from infections- especially viral).

Risk Factors for GVHD following UCB transplantation: Single or Double Unit Cord Transplant?

One or Two Cords, if GVHD is the only consideration?

BMT CTN 0501: Single vs. Double UCB in Pediatric Patients

• Multi-center randomized study of 1 (n=113) vs. 2 units (n=111). • Conditioning: Flu/Cy/TBI (1320 cGY) • GVHD Prophylaxis: CSA/MMF • Median TNC: 4.8 vs. 8.8 X 107/kg

Single UCB Double UCB p- value

Overall Survival @ 1 year 71% 66% 0.13

Relapse @ 1 year 12% 14% 0.37

NRM @ 1 year 20% 22% 0.45

Neutrophil Recover at day 42 89% 87% 0.08

Platelet Recovery at day 180 80% 72% 0.06

Acute GVHD II-IV at day 100 57% 57% 0.94

Acute GVHD III/IV at day 100 14% 23% 0.03

Any Chronic @ 1 year 32% 30% 0.64

Higher Acute GVHD III/IV; but no impact on NRM

Risk Factors for Grade II-IV Acute GVHD following unrelated donor umbilical cord transplantation (multiple regression analysis)

Factor RR for acute GVHD (95% CI) P Number of Donors One Two

1.0

2.0 (1.2-3.4)

0.01

Conditioning Regimen Myeloablative Nonmyeloablative

1.0

1.7 (1.1-2.5)

0.01

ATG in Conditioning No Yes

1.0

0.5 (0.3-0.9)

0.02

MMF as prophylaxis No Yes

1.0

0.5 (0.2-1.3)

0.14

HLA-Match (engrafted unit) 6/6 5/6 4/6

1.0

1.9 (0.9-4.2) 1.4 (0.7-3.2)

0.11 0.36

University of Minnesota examined the relative risk of acute GVHD in 265 consecutive UCB transplants (Single / Double Unit UCBT: 80 / 185) in patients > 10 years of age between 1994-2006.

MacMillan M L et al. Blood. 2009. 113:2410-2415

Cumulative incidence of Grade II-IV acute GVHD: 2-Fold Increased Risk in Double UCBT

MacMillan M L et al. Blood. 2009. 113:2410-2415

Maximum stage of acute GVHD by organ system in recipients of a single and double UCB transplant

Higher Incidence in Double solely due to > skin Stage 3

MacMillan M L et al. Blood. 2009. 113:2410-2415

Lower GI Upper GI

Cumulative incidence of TRM at 1 year after

transplantation: TRM always worst after Single Unit All Patients Patients with Grade II-IV acute GVHD

• If you get acute GVHD, better to have 2 cord.

• In MV analysis, only factor impacting TRM following acute GVHD was receipt of Double versus Single (RR 0.4; 0.2-0.9, p=0.03).

• While Risk of Grade III/IV GVHD was similar between Single versus Double, TRM was twice as high in those who get it following Single Unit UCBT. (Single 43% vs. Double 20%, p=0.06)

MacMillan M L et al. Blood. 2009. 113:2410-2415

Caution: Recent Results from MSK examining GVHD after DUBCT

Characteristic Value

Median Age, years 37 (1-69)

Diagnosis Acute Leukemia Lymphoma/ CLL MDS/ CML/ other MPD

58% 37% 5%

Conditioning Ablative RIC NMA

49% 28% 23%

GVHD Prophylaxis CNI + MMF

100%

ATG 0%

Patient Characteristics (n=115)

Grades II to IV and III to IV acute GVHD at day 180

Ponce et al. BBMT. 2013.

Organ Involved N (%)

Gastrointestinal Upper Only Lower Only Upper & Lower

49 (80%) 14 (29%) 9 (18%) 26 (53%)

Skin Stage II Stage III Stage IV

39 (64%) 20 (51%) 17 (44%) 2 (5%)

Liver 9 (18%)

Is GVHD worst after DUCBT?

• Caution should be used when interpreting single-center reports.

• Many factors can influence GVHD including use of ATG, Different Conditioning Regimens and difference in reporting/ confirming GVHD.

Risk Factors for GVHD following UCB transplantation: Single or Double Unit Cord Transplant?

One or Two Cords, if GVHD is the only consideration?

Children: One seems to be as good (or better than 2, less Grade III/IV).

Adults: Would not base this on risk for GVHD Acute GVHD rates are higher with 2 cords, but

TRM lower (in one single-center report) and other factors (engraftment) probably more important.

Is Treatment-Related Mortality Following development of acute GVHD influence by stem cell source?

Is it worst for recipients of Cords?

Recipients of Single or Double UCB who develop acute GVHD do not have higher TRM when compared to acute GVHD after receipt of another donor source.

MacMillan et al. Blood. 2010. 115: 5412-7.

Treatment Related Mortality after Acute GVHD Based on Donor

Donor Type Relative Risk

(95% CI)

p Matched Sibling 1.O (reference)

Matched Unrelated Donors 1.42 (0.92-2.20) 0.11

Unrelated or Sibling Mismatched 1.88 (1.34-2.63) <0.001

Single Umbilical Cord 1.18 (0-72-1.94) 0.52

Double Umbilical Cord 0.74 (0.44-1.2) 0.21

Is Acute GVHD after UCB more responsive to treatment?

Ponce et al. BBMT. 2013.

61 patients with Grade II-IV Acute GVHD Systemic Steroids: 29 patients

• Gd II: 28% • Gd III: 55% • Gd IV: 17%

Budesonide Alone: 27 patients • Grade II: 100%

Day 28 GVHD Response • CR: 38% • PR: 41% • <PR: 21%

Day 28 GVHD Response • CR: 37% • PR: 48% • <PR: 15%

Ponce et al. BBMT. 2013.

Is Upper GI GVHD after cords more Responsive to Budesonide? Original Work in Seattle with Non-Absorbable steroids

suggested that they do not work when administered alone (randomized study with beclomethasone called for concurrent treatment with brief period of systemic steroids).

What does day 28 response mean for entity upper GI GVHD? How can you have a PR?? How do you assess this response retrospectively?

Think suggestion that Budesonide-alone results in “high day 28 response” needs to be interpreted with significant caution.

Is Cord GVHD More Steroid Responsive?

Japanese Registry paper suggested patients with acute GVHD after a UCBT were more likely to “respond” than after MRD, MUD, or MM Unrelated.

However, “response” was defined as not receiving second-line

therapy and results should be interpreted cautiously. Series from Univ. of Minnesota (MacMillan et al. Blood. 2009)

suggest acute GVHD might be more responsive to steroids.

Is Acute GVHD after UCB more responsive to treatment?

Answer: Maybe, certainly not worst

Does Chronic GVHD rates and presentation differ following Umbilical

Cord Transplantation?

Chronic GVHD following Umbilical Cord Transplantation

• Chronic GVHD is leading the cause of late Non-Relapse Mortality after transplantation.

• Recently Peripheral Blood was found to result in higher rates of chronic GVHD than Bone Marrow in Matched Unrelated Donor recipients.

• UCB results in lower rates of chronic GVHD when compared to MUD.

• Main Risk factors for Chronic GVHD following Cord is h/o Acute GVHD (especially severe).

• By NIH Criteria, the classic form of chronic is low in cord recipients (5%) with late acute (71%) and Overlap (24%) variants predominating. Alsultan et al. BMT. 2011. 46: 668-75.

Umbilical Cord Recipients who get Chronic GVHD are more likely to respond to GVHD therapy than MUD’s

Predictors of Chronic GVHD response at 2 months following Diagnosis

Predictor Odds Ratio (95% CI) P

Umbilical Cord Blood versus MUD 3.8 (1.3-11.1) 0.02

De novo or Quiescent Onset 3.2 (1.1-9.3) 0.03

Predictors of Chronic GVHD response at 2 years following Diagnosis

Umbilical Cord Blood versus MUD 6.6 (1.9-23.3) 0.003

De novo or Quiescent Onset 3.8 (1.1-12.8) 0.03

Arora et al. BBMT. 2007. 13: 1145-1152.

Overall Survival, Disease-Free Survival, Relapse and Non-relapse Mortality in Patients who develop Chronic GVHD after UCB vs. MUD

Non-relapse Mortality following Chronic GVHD: lower in recipients of UCB vs. MUD’s.

27 vs. 11% at 1 year

Arora et al. BBMT. 2007. 13: 1145-1152

Discontinuation of Immunosuppressive Medications: Despite Higher Response Rates in UCB Cumulative Incidence

and Timing of Discontinuation Similar to MUD’s

Roughly 1/4th of Chronic GVHD patients on immunosuppressive medications beyond 4 years

Arora et al. BBMT. 2007. 13: 1145-1152.

Can we utilize properties of Umbilical Cords to treat or prevent

GVHD?

Prophylactic infusion of Ex-Vivo Expanded 3rd party Cord Blood Treg

prevents GVHD

Studies demonstrate that cord blood as compared to adult blood is an improved source for Treg-cell isolation and culture.

• Previous studies have shown that ex vivo polyclonally expanded Treg cells can be effective in preventing or suppressing GVHD.

• In some models, Treg cells can prevent GVHD and still allow GVL.

• Consequently, T reg cells could have a potential role in clinical immunosuppressive therapy in transplantation, provided human Treg cells could be isolated and expanded to generate sufficient numbers for in vivo infusion.

• Adult human Treg studies are impeded by contamination of CD25 dim expressing T-cells.

Godfrey et al. Blood. 2005. 105: 750-758.

Cultured cord blood–derived CD4+CD25+ cells markedly suppress MLRs. Analysis of suppressor cell function in MLR assays by

proliferative inhibition.

Patient Eligibility: Phase I UCB Treg Trial in UCB Transplant Recipients

ABO Compatible

Brunstein, C., Blood 117:1061-70, 2011

HLA: 4-6/6

Treg

HLA: 4-6/6

HLA: 4-6/6 HLA: 4-6/6

-18

MMF

UCB stem & T cells

Phase I Treatment Plan for Human UCB Tregs

CSA or Rapa

Phase I semi-log dosing: 1 – 30 x 105/ kg/dose

Non-myeloablative conditioning

UCB Tregs Treg cell UCB

culture UCB Tregs

0 +1 -9 ... -3 ... Days Post-Transplant

+15

Grade II-IV Acute GVHD

Cum

ulat

ive

Inci

denc

e

Historical 60%

Treg

43%

0.0

0.2

0.4

0.6

0.8

1.0 P = 0.05

Viral + Fungal Infections

Days Post-Transplant

Historical 67%

Treg 39%

0 20 40 60 80 100

P = 0.02

Relapse at 1 year

P = 0.43

Historical 48%

Treg

35%

0 180 360 270 90 0 20 40 60 80 100

Major Outcomes of Phase I Treatment Plan

Primary Endpoint: No Dose-Limiting Toxicities Seen

Lab of Simrit Parmar, MD Xiaoying Liu

Shawndeep Tung Simon Robinson

MD Anderson Cancer Center

Dept. of SCTCT Richard Champlin, MD

EJ Shpall, MD Marcos DeLima, MD

Yago Nieto, MD Simrit Parmar, MD

Partow Kebriaei, MD Uday Popat, MD Nina Shah, MD

Roy Jones, MD, PhD Borje Andersson, MD Martin Korbling, MD Paolo Anderlini, MD

Issa Khouri, MD Chitra Hosing, MD

Muzaffar Qazilabsh, MD Stefan Ciurea, MD

Geath Al-Atrash, DO, PhD G. Rondon, MD