Thalassemia study with stem cells

Phase 2

Not yet recruiting

Conditions: High-risk Thalassemia undergoing allogeneic stem cell transplant

Registration Number: CTRI/2018/07/014826

Lead Sponsor: Christian Medical College Vellore

Brief Summary: Graft-versus-hostdisease (GVHD) is a frequent complication arising post-allogeneic stem celltransplant, related to antigenic differences between the donor and host cells.GVHD can range from a mild skin rash not requiring systemic immunosuppression,to life-threatening multi-organ dysfunction requiring multiple lines ofimmunosuppression and subsequent risks of infection.

The currentstandard of care for GVHD prophylaxis in patients undergoing allogeneic stemcell transplant with myeloablative conditioning regimens is the combined use ofCyclosporine/Methotrexate or Tacrolimus/Methotrexate which in combination have been shown to reduce the incidence of acute and chronicGVHD.

The risksassociated with allogeneic transplant in Thalassemia Major vary depending ondefined critieria, namely, liver size, adequacy of chelation and presence ofliver fibrosis. We have shown that a subset of patients have a higher risk ofdeveloping transplant-related complications - older children (>7years) andthose whose palpable liver size exceeds 7cm. Myeloablative conditioning results in severe liver dysfunction (veno-occlusivedisease) in these patients who already have a baseline compromised hepaticfunction (due to iron overload).

Current GVHD prophylaxisinduces further hepatic dysfunction, often nessecitating dose modification/omissionof drugs (especially methotrexate) to limit the hepatic toxicity. CompromisedGVHD prophylaxis then results in higher rates of both acute and chronic GVHD inthese patients.

This studywill study the impact of a non-hepatotoxic GVHD prophylaxis in reduction ofliver dysfunction and rates of reduce acute and chronic GVHD in these high-riskpatients. Cyclophosphamide has previouslybeen been used as GVHD prophylaxis inthe setting of Haplo-identical stem cell transplants,as well as in aplastic anemia,and has shown comparable rates of GVHD.

This will be a Randomized Phase II trial comparingHigh-dose Cyclophosphamide as sole GVHD prophylaxis with standard of care(Cyclosporine/MTX) in patients with CLASS III High-Risk Thalassemia Major.

After randomization, all patients will be treated withstandard precautions that apply to all patients undergoing allogeneic stem celltransplant at our institution.

**Graft versus host disease prophylaxis:**

As per randomization **ArmA**: On Day+3 and Day +4, Cyclophosphamide 25mg/kg will be administered over 1hrs,and hydration (3lts/m2) along with MESNAat eqivualent doses (20% stat and 50% Q12H till 12hrs post-cyclophosphamide) toprevent the development of haemorrhagic cystitis. Intake and urine output willbe carefully monitored during this time and adequate diuresis will be ensured,with the addition of diuretics as and when required. Intravenous Cyclosporine 2.5mg/kgwill be given over 4hours twice daily, until resolution of mucositis, when thecyclosporine will be given orally, targeting a trough level of100-300ng/ml, to continue for 3mths, and tapered by 6mths.

**ARM B:** Cyclosporine andshort course methotrexate current protocol: Cyclosporine will be administeredat a dose of 2.5 mg/Kg intravenously over four hours twice daily starting onday â€“4 and will be changed to oral administration at 5 mg/Kg twice daily whenmucositis resolves. Cyclosporine levels will be monitored and the dose adjustedto achieve a target level of 100â€“300 ng/ml. Cyclosporine is continued till9mths, and tapered by 1 year. Methotrexate will be given at the followingdoses: 10 mg/m2 on day +1 and 7 mg/m2 on day +3, +6 and +11.

**Chimerism studies:** Chimerism analysis will be done forall patients on Day 28, Day 60 and Day 100 on whole blood by PCR, by polymerase chain reaction amplification ofinformative STR or VNTR followed by gene scan analysis.

**Supportive care:** All patients will benursed in a positive pressure HEPA filtered transplant unit. None of thepatients will receive prophylactic antibiotics or underwent gutdecontamination. Prophylactic acyclovir will be administered for the first 100days; it will be continued beyond day 100 if patient has GVHD and requiresadditional immuno-suppression. Trimethoprim-sulfamethoxazole and oralpenicillin prophylaxis will be initiated after stable engraftment and continuedfor a year. At the end of one year all patients who do not have evidence of GVHDand are off all immunosuppressive drugs will be vaccinated against polio,diphtheria, tetanus, hemophilus influenza and pneumococcus.

**Primary Outcome:**

Incidence of chronic GVHD at 1 year (chronic GVHDdefined according to NIH criteria)

**Secondary Outcomes:**

Incidence and severity of acuteGVHD

Incidence of CMV reactivation (definedas 2 consecutive quantitative PCRs with CMV copy number >1000 copies/ml ofwhole blood)

Event-free survival at 1 year(Event defined as rejection or death for the purpose of this study)

GVHD-free survival (Defined assurvival without ongoing GVHD as assessed at 1year post-transplant)

**Sample size:**

Based on the data from our institution, the rate of acute and chronicGVHD is approximately 50% with the present GVHD prophylaxis which is standardof care. With a change in GVHD prophylaxis, we intend to decrease the incidenceof chronic GVHD from 50% to 20% in chronic GVHD (assessed till 1year). With 5%significance and 80% power, the required sample size will be 38 patients ineach arm. After a written informed consent, all high risk patients will beenrolled in the study prospectively.

As this is a preliminaryexploratory efficacy study, it is a Phase II trial, and if the data ispromising, we plan to conduct a Phase III multicenter trial, as patient numbersat a single center will not be adequate for a Phase III trial.

Detailed Description: Not available

Recruitment & Eligibility

Status: Not Yet Recruiting

Sex: All

Target Recruitment: 76

Inclusion Criteria

Signed and dated written informed consent by start date of Screening visit in accordance with GCP and local legislation 2.
Patients with High Risk Thalassemia (Defined as having both Age >7yrs and Liver size >5cm) who are planned for allogeneic stem cell transplantation.

Exclusion Criteria

Cardiac dysfunction as assessed by ECHO and Cardiac MRI pre-transplant.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Incidence of chronic GVHD at 1 year (chronic GVHD defined according to NIH criteria)	Incidence of chronic GVHD at 1 year (chronic GVHD defined according to NIH criteria)

Secondary Outcome Measures

Name	Time	Method
Incidence and severity of acute GVHD	Acute GVHD at 100 days

Trial Locations

Locations (1): Christian Medical College, Vellore
🇮🇳
Vellore, TAMIL NADU, India
Christian Medical College, Vellore
🇮🇳Vellore, TAMIL NADU, India
Vikram Mathews
Principal investigator
04162282352
vikram@cmcvellore.ac.in