Introduction
There has been a significant change in the survival rates of patients
with childhood leukemias over the past few decades. The five-year
survival rate for ALL has been documented to be over 95% while the same
for childhood AML, long term survival is currently 70% or
higher1,2. The state of the relapsed disease is still
guarded. In case of childhood AML, 24-40% of patients relapse, with an
approximately 30% chance of survival. Recent data points towards a
five-year OS of 50% in childhood ALL at first
relapse3. The armamentarium of therapeutic options for
relapsed acute leukemias have expanded to include several therapeutic
options, including newer monoclonal antibodies and CAR T cell therapy,
but salvage chemotherapy followed by hematopoietic stem cell
transplantation remains the mainstay of treatment in resource limited
settings.
The choice of salvage regimens is influenced by several factors,
including the dose of anthracyclines received previously and the balance
between the perceived benefit and potential toxicity. One of the most
significant challenges posed during salvage chemotherapy is the
translocation of gut bacteria and neutropenic sepsis secondary to it.
Hence there is a need for a chemotherapeutic regimen that limits
exposure to anthracyclines while at the same time reducing the gut
toxicity1.
The combination chemotherapy regimen FLAG (Fludrabine, Cytarabine and G
CSF) has been studied in the setting of relapsed leukemia in several
studies4,5. Fludrabine was found to have a synergistic
effect with Cytarabine, by increasing the rate of production of its
active metabolite 5’-triphosphate ara-CTP6. GCSF used
in this combination further sensitizes the leukemic cells to the
cytotoxic effects of Cytarabine, by recruiting the leukemic cells into
the S phase and potentiating the incorporation of ara C metabolites into
the cell and the subsequent ara C induced apoptosis7.
Historically Idarubicin, has been used in combination with the FLAG
regimen, but there has been evidence supporting the use of the
proteosome inhibitor Bortezomib in its place. The use of Bortezomib has
shown to have complete remission rates of more than 70% in several
studies8, reducing the exposure to anthracyclines and
potentially reducing gut toxicity, makes this combination an attractive
option in the relapsed setting, especially in the resource limited
setting.
We are reporting our experience with this combination therapy.
Patients and Methods
We performed a retrospective analysis in the Department of Pediatric
Hematology and Bone Marrow Transplant from January 2021 to June 2023. 12
patients of relapsed refractory AML/ALL (One patient had CML in blast
crisis) were included in the analysis. All patients received at least
one cycle of FLAG with Bortezomib. The toxicity profile analysed was the
incidence of sepsis, the need for ICU admission or treatment related
mortality. Morphological remission in the bone marrow and MRD status,
performed at count recovery.
Chemotherapy Protocol
GCSF was given at 5 microgram/kg/day subcutaneously from Day 1 to Day 7,
Fludrabine was given at a dose of 30mg/m2 as an infusion over 30 minutes
from days two to six and Cytarabine (2gm/m2) was given daily as an
intravenous infusion over 4 hours. Fludrabine was given 4 hours
preceding the Cytarabine infusion. Bortezomib at a dose of 1.3mg/m2 was
given on days 1, 4,8 and 11 as an intravenous bolus push.
All patients received prophylactic antifungals and antivirals.
Prophylaxis for pneumocystis jirovecii was also initiated for all
patients.
Assessment of Response
Bone marrow examination was performed at the onset of neutrophil
recovery (absolute neutrophil count of >1000 cells/mm3).
Morphological remission was defined as <5% blasts on bone
marrow examination with evidence of normal haematopoiesis. Complete
remission was defined as morphological remission with a negative MRD
study by flow cytometry.
The primary end point was remission status after the FLAG- Bortezomib
regimen and the requirement of ICU admission, presence of neutropenic
sepsis and treatment related mortality were secondary end points.
Statistical Analysis
Categorical variables were represented by percentage. Continuous
variables were expressed as mean± SD. Comparison of categorical
variables were done by either χ2 test or Fisher exact test based on the
number of observations. Comparison of continuous variables between the
groups were done by independent sample “t” test. Data entry were done
in MS Excel sheet. Data validation and analysis were carried out in SPSS
version 25.0. All “P”-values <0.05 was considered as
statistically significant.
Results
Our study population included 12 patients, with a mean age of 8.3 years.
The male to female ratio was 2:1 (8 male patients and 4 female
patients). There were six patients with refractory AML, five patients
with relapsed/refractory ALL, one patient was a case of CML in myeloid
blast crisis. Nine patients received one cycle each of FLAG with
Bortezomib, while two patients received a second cycle of induction,
patient characteristics are shown in table 1.
All children included in the study had episodes of febrile neutropenia.
Seven of the children had positive blood cultures (58.3%). Klebsiella
pneumoniae was the most common organism grown, in four patients
(~33%), E Coli was grown in two patients during first
induction while Acinetobacter species was grown in cultures obtained
from one patient. Two patients received a second induction with FLAG
Bortezomib, and one of the patients had culture positive sepsis with E
coli species grown in the culture. Despite the incidence of sepsis and
febrile neutropenia, only three patients required ICU admission during
induction.
Seven patients (58.3%) had a documented morphological remission after 1
cycle of salvage therapy. Two patients went on to receive a second
course of induction regimen, in view of MRD positivity and persistent
blasts respectively. The child with persistent disease went on to
achieve complete remission, and the MRD positivity was significantly
reduced in the second child. Among all patients, six children had
achieved complete remission (50%). A total of eight patients
(66.6%) went onto to undergo an allogenic HSCT. One patient succumbed
to treatment related sepsis during induction with FLAG Bortezomib.
Discussion
Remission induction in the relapsed refractory setting poses several
challenges, especially in the face of limited resources. Prolonged
hospitalization and the additional costs of antibiotics during the
treatment course are factors that have been shown to significantly
impact the rates of treatment discontinuation in childhood
cancers9. The rationale for use of Bortezomib in
combination with chemotherapy for remission induction, was based on the
premise that proteosome inhibition by Bortezomib could potentially
sensitize the malignant cells to chemotherapy induced apoptosis, by
proteosome inhibition10. Pre-clinical studies have
shown the efficacy of Bortezomib in combination with chemotherapy in the
treatment of childhood leukemia. Horton et al, had reported on the
increased efficacy of Bortezomib in combination with chemotherapy, while
an overall response rate of upto was demonstrated in the therapeutic
advances in leukemia and lymphoma study8,10.Bertainia
et al had shown that the addition of Bortezomib to the classical four
drug induction therapy was associated with a complete response rate of
72.9% but was associated with the occurrence of
neuropathy11. The omission of Vincristine was
associated with significantly less neuropathy as demonstrated in an
Indian study, which showed response rates of 88% in second remission,
with a combination of Bortezomib and reduced dose
Cytarabine12. Ravindran et al had studied 12 patients
treated with the combination of FLAG and Bortezomib,92% of their
patients had attained morphological remission1. While
the rates of morphological remission was lower in our population, a
significant proportion of our patients went onto receive a successful
HSCT, with minimal treatment related mortality in the remission
induction phase. In a resource limited setting, an accessible regimen
with a favourable toxicity profile, can improve the accessibility of
care in this difficult to treat population of patients.
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