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Graft-versus-host
disease (GVHD) is a frequent complication arising post-allogeneic stem cell
transplant, 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 of
immunosuppression and subsequent risks of infection.
The current
standard of care for GVHD prophylaxis in patients undergoing allogeneic stem
cell transplant with myeloablative conditioning regimens is the combined use of
Cyclosporine/Methotrexate or Tacrolimus/Methotrexate which in combination have been shown to reduce the incidence of acute and chronic
GVHD.
The risks
associated with allogeneic transplant in Thalassemia Major vary depending on
defined critieria, namely, liver size, adequacy of chelation and presence of
liver fibrosis. We have shown that a subset of patients have a higher risk of
developing transplant-related complications - older children (>7years) and
those whose palpable liver size exceeds 7cm. Myeloablative conditioning results in severe liver dysfunction (veno-occlusive
disease) in these patients who already have a baseline compromised hepatic
function (due to iron overload).
Current GVHD prophylaxis
induces further hepatic dysfunction, often nessecitating dose modification/omission
of drugs (especially methotrexate) to limit the hepatic toxicity. Compromised
GVHD prophylaxis then results in higher rates of both acute and chronic GVHD in
these patients.
This study
will study the impact of a non-hepatotoxic GVHD prophylaxis in reduction of
liver dysfunction and rates of reduce acute and chronic GVHD in these high-risk
patients. Cyclophosphamide has previously
been been used as GVHD prophylaxis in
the 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 comparing
High-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 with
standard precautions that apply to all patients undergoing allogeneic stem cell
transplant at our institution.
Graft versus host disease prophylaxis:
As per randomization Arm
A: On Day+3 and Day +4, Cyclophosphamide 25mg/kg will be administered over 1hrs,
and hydration (3lts/m2) along with MESNA
at eqivualent doses (20% stat and 50% Q12H till 12hrs post-cyclophosphamide) to
prevent the development of haemorrhagic cystitis. Intake and urine output will
be carefully monitored during this time and adequate diuresis will be ensured,
with the addition of diuretics as and when required. Intravenous Cyclosporine 2.5mg/kg
will be given over 4hours twice daily, until resolution of mucositis, when the
cyclosporine will be given orally, targeting a trough level of
100-300ng/ml, to continue for 3mths, and tapered by 6mths.
ARM B: Cyclosporine and
short course methotrexate current protocol: Cyclosporine will be administered
at a dose of 2.5 mg/Kg intravenously over four hours twice daily starting on
day –4 and will be changed to oral administration at 5 mg/Kg twice daily when
mucositis resolves. Cyclosporine levels will be monitored and the dose adjusted
to achieve a target level of 100–300 ng/ml. Cyclosporine is continued till
9mths, and tapered by 1 year. Methotrexate will be given at the following
doses: 10 mg/m2 on day +1 and 7 mg/m2 on day +3, +6 and +11.
Chimerism studies: Chimerism analysis will be done for
all patients on Day 28, Day 60 and Day 100 on whole blood by PCR, by polymerase chain reaction amplification of
informative STR or VNTR followed by gene scan analysis.
Supportive care: All patients will be
nursed in a positive pressure HEPA filtered transplant unit. None of the
patients will receive prophylactic antibiotics or underwent gut
decontamination. Prophylactic acyclovir will be administered for the first 100
days; it will be continued beyond day 100 if patient has GVHD and requires
additional immuno-suppression. Trimethoprim-sulfamethoxazole and oral
penicillin prophylaxis will be initiated after stable engraftment and continued
for a year. At the end of one year all patients who do not have evidence of GVHD
and 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 GVHD
defined according to NIH criteria)
Incidence and severity of acute
GVHD
Incidence of CMV reactivation (defined
as 2 consecutive quantitative PCRs with CMV copy number >1000 copies/ml of
whole blood) Event-free survival at 1 year
(Event defined as rejection or death for the purpose of this study)
GVHD-free survival (Defined as
survival without ongoing GVHD as assessed at 1year post-transplant) Sample size:
Based on the data from our institution, the rate of acute and chronic
GVHD is approximately 50% with the present GVHD prophylaxis which is standard
of care. With a change in GVHD prophylaxis, we intend to decrease the incidence
of 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 in
each arm. After a written informed consent, all high risk patients will be
enrolled in the study prospectively.
As this is a preliminary
exploratory efficacy study, it is a Phase II trial, and if the data is
promising, we plan to conduct a Phase III multicenter trial, as patient numbers
at a single center will not be adequate for a Phase III trial.
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