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.