Discussion:
In case of relapse or primary non-response to therapy, acute leukemias
have a very poor prognosis. The aim in these cases is to achieve a
remission by a salvage therapy and subsequently performing an allogeneic
hematopoietic stem cell transplantation. In case of a first relapse of
AML in children, the chemotherapeutic drugs daunorubicine, cytarabine,
idarubicine and fludarabine are used according to the International
Registry AML Relapse 2009 10. In case of primary
refractory or relapsed ALL in children cyclophosphamide, cytarabine,
asparaginase, daunorubicine, corticosteroids, vincristin, methotrexate,
idarubicine, thioguanine, ifosfamide are used according to the ALL REZ
BFM 2002 protocol 4. Currently different salvage
therapies are tested with the aim to find a potentially curative therapy
for the cases in which no complete remission can be achieved with
standard chemotherapeutic regimens. In case of relapsed or refractory
B-cell precursor leukemia the treatment with the immunomodulatory
antibody blinatumomab could lead to a complete remission rate of 39%
and a two year overall survival rate of 20% in a phase 1 – 2
multicentre study with 70 pediatric patients 11,12.
Recently the treatment with Chimeric Antigen Receptor (CAR)-T-cells is
investigated in several studies. The use of these genetically modified
immune cells in the therapy of relapsed / refractory CD 19-positive ALL
resulted in an one year overall survival rate of 76% in a phase 2
multicenter study including 75 pediatric or young adult patients13.
The patients in our case cohort had been extensively pre-treated, all
patients had received at least three regimens of chemotherapy before the
salvage therapy with melphalan / cytarabine. All patients with ALL had
received one or more cycles of blinatumomab. No patient had received a
therapy with CAR-T-cells prior to the salvage therapy with melphalan /
cytarabine, as they were not yet available. 50% of the patients had
already received an allogeneic HSCT. The patients displayed a very high
cumulative therapeutic burden. This is the reason why we chose a low
dosage of melphalan (1 x 20 mg/m²) and cytarabine (10 x 100 mg/m² as
continuous infusion) in one case and in two cases we only reduced the
dosage of cytarabine.
The reported toxicity in this case collection was low, 25% of patients
experienced a temporary period of high fever and SIRS, no pathogen could
be identified. One patient experienced a derangement of blood
coagulation without other signs of SIRS. In one case a temporary
increase of liver enzymes was reported. Cytarabine is known to cause
temporary high fever, an increase of liver enzymes can be caused by
melphalan as well as cytarabine 6,9.
The more chemotherapeutic regimens have failed to achieve a remission,
the less likely achievement of a complete remission becomes. A possible
explanation would be the formation of chemotherapy resistant leukemic
clones. Accordingly, Gorman and his colleagues reported a complete
remission rate of 17% in their retrospective study including 99
patients with multiply-relapsed AML following the fourth treatment
attempt3.
In primary relapse the response rates in AML and ALL are distinctively
higher: In a retrospective study evaluating the outcome of children with
primary relapsed or refractory acute myeloid leukemia a five year
survival rate of 34% was reported after a re-induction therapy with
6-thioguanine, cytarabine, doxorubicin, etoposide and mitoxantrone
according to the NOPHO-88 an NOPHO-93 trials 14.
The use of fludarabine, high dose cytarabine, G-CSF (FLAG) and in some
cases additional liposomal daunorubicin (L-DNR/FLAG) according to the
International study Relapsed AML 2001/01 trial including 155 pediatric
patients with primary relapsed AML and 10 pediatric patients with
primary refractory AML lead to four year survival rates of 43%
(L-DNR-FLAG) and 47% (FLAG)15. L-DNR/FLA without
G-CSF is also recommended for patients with refractory ALL according to
the AIEOP-BFM ALL 2009 protocol, leading to a MRD reduction <
5x10-4 in 50% of the cases 16.
A complete remission rate of 68%, a five year overall survival rate of
24% and a toxicity rate ≥ grade 3 of 96% was reported in a
retrospective single-center study including 53 pediatric patients with
primary relapsed (68% of cases) or multiply-relapsed (32% of cases)
AML or ALL after a salvage therapy with FLAG ± idarubicin (IDA)17. Keshu Zhou and his colleagues reported a two year
overall survival rate of 30% in their study analysing the outcome of
patients with acute lymphoblastic leukemia in primary refractory cases
(36%), in the first relapse (52%) or in the second relapse (11%)
after a salvage therapy with granulocyte-colony stimulating factor
(G-CSF), low dose cytarabine and aclarubicin 18.
The response rate in the present case collection is in line with the
above mentioned studies: In 63% of our patients complete or partial
remission could be achieved with the possibility to perform an
allogeneic HSCT. The one year survival and the three year survival rates
were 50% and 29%. It should be considered that it was the second or
third relapse in three patients, the first relapse in two patients and
three patients were primarily refractory and in addition all patients
had received at least three previous therapy regimens.
Melphalan has so far mainly been used in conditioning regimens prior to
stem cell transplantations. To our knowledge, it has not yet been used
as a chemotherapy block with the aim of remission induction and
subsequent conditioning for stem cell transplantation in primary
refractory or multiply-relapsed AML or ALL. In the presented study we
used melphalan as a salvage therapy in a median dosage of 40 mg/m² in
one administration. Steckel et al. reported an overall survival rate of
34% in primary refractory and 41% in relapsed AML in their study
including 292 adult patients with AML. The patients in their study
received a conditioning regimen with melphalan in a dosage of 140 mg/m²
in combination with fludarabine and a total body irradiation19. In another retrospective study the outcome after a
conditioning regimen with melphalan in a dosage of 2 x 70 mg/m² in
combination with clofarabine and thiotepa and immediate subsequent stem
cell transplantation was examined. This study included 18 pediatric and
adult patients with AML or ALL in first or second relapse after an
initial HSCT. The three year overall survival was 49% and the therapy
related mortality was 11% 20. The results of our case
cohort analysis indicate that melphalan could also lead to a
cytoreductive effect in lower, non myeloablative doses, with the
possibility of subsequent stem cell transplantation.