Central nervous system relapse after allogeneic HCT in FLT3-mutated AML

doi:10.21203/rs.3.rs-4953532/v1

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Central nervous system relapse after allogeneic HCT in FLT3-mutated AML

https://doi.org/10.21203/rs.3.rs-4953532/v1

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Central nervous system (CNS) relapse in acute myeloid leukemia (AML) is rare, but prognostically extremely unfavorable and associated with very high mortality rates. Aim of our single-center study was to define risk factors for CNS relapse in patients with FLT3-mutated AML after allogeneic hematopoietic cell transplantation (HCT) and to determine the impact of pre-emptive or salvage therapy with FLT3-inhibitors (FLT3i) on occurrence of CNS relapse and overall prognosis.

We analyzed 39 FLT3-mutated AML patients who were treated with intensive induction therapy and consecutively underwent HCT at our institution. We observed that the remission status before HCT was strongly associated with relapse probability. Notably, FLT3-mutated AML showed a high propensity for CNS relapse with a cumulative incidence of 50% (95% confidence interval [CI], 16–77) at 2 years in non-responders pre-HCT compared to 0% in responders (cause-specific hazard ratio, 24.5, 95% CI, 2.9-206.2; p = 0.003). This was not abrogated by pre-emptive or salvage therapy with FLT3i in first relapse.

Targeted therapies prior to transplant, use of intrathecal chemoprophylaxis or closer monitoring may be considered in patients with FLT3-mutated AML with active disease prior to HCT in order to prevent CNS relapse. Additionally, CNS directed induction therapies may be indicated.

FLT3

AML

HCT

CNS

relapse

Real-World Data

Retrospective

Nearly 30% of AML patients harbor a FMS-like tyrosine kinase 3 (FLT3) gene mutation. (1) The increased relapse risk and unfavorable outcomes associated with FLT3 internal tandem duplications (ITD) may be counteracted by treatment with specific FLT3 inhibitors (FLT3i) and allogeneic hematopoietic cell transplantation (HCT). (2) In contrast, mutations in the FLT3 tyrosine kinase domain (TKD) do not appear to negatively influence the prognosis. (3) The discovery of FLT3 mutations and their prognostic significance led to the development of numerous targeting compounds: The multiple tyrosine kinase inhibitor midostaurin, in combination with standard induction and consolidation chemotherapy was shown to improve overall survival (OS). (4) Sorafenib is recommended as maintenance therapy post-transplant irrespective of measurable residual disease (MRD) prior to transplant. (5, 6) The second-generation FLT3 inhibitor gilteritinib was approved as monotherapy in relapsed or refractory FLT3-mutated AML. (7) Using quizartinib in addition to standard chemotherapy and for maintenance has also contributed to better overall survival in patients with newly diagnosed FLT3-mutated AML. (8) Overall, FLT3i have significantly impacted AML treatment, improving overall survival rates.

The efficacy of FLT3i in extramedullary disease including CNS involvement remains unclear. In general, CNS involvement in AML is rare and associated with increased risk of morbidity and mortality with a 5-year OS of only 11%. (9) The exact incidence of CNS involvement in adult patients with AML is unknown, as routine cerebrospinal fluid (CSF) sampling is rarely performed in neurologically asymptomatic patients. Risk factors for CNS involvement in AML identified so far include high white blood cell count (WBC) and elevated lactate dehydrogenase (LDH) at first diagnosis, (9, 10) but little is known about risk factors for CNS relapse after HCT. Aim of this retrospective single center study was to evaluate the frequency of CNS relapse in patients with FLT3-mutated AML who underwent HCT, to determine underlying risk factors and to analyze the impact of FLT3-targeted therapies.

Inclusion criteria for this retrospective study were adult patients with FLT3-mutated AML (FLT3-ITD and/or FLT3-TKD) and first HCT between January 2017 and December 2020 at our transplant center at Goethe University Hospital Frankfurt, Germany. Primary endpoint of the study was the cumulative incidence of CNS relapse.

Clinical data including conditioning regimens and pre-emptive and maintenance therapy with FLT3i were retrospectively retrieved from electronic health records. Conditioning regimens for HCT were defined as myeloablative (MAC), non-myeloablative (NMA) or reduced intensity (RIC) according to Bacigalupo et al. and Giralt et al. (11, 12). Treatment response was defined according to the European Leukemia Network (ELN) 2017 criteria as bone marrow blasts < 5% in the absence of circulating blasts and extramedullary disease, either with complete (CR) or incomplete (CRi) hematologic recovery (absolute neutrophil count [ANC] ≥ 1.0×10⁹/L, platelet count ≥ 100×10⁹/L). (2) Measurable residual disease (MRD), was determined prior to and 60–100 days after allogeneic HCT by RT-qPCR (NPM1mut, n = 26; KMT2A-PTD, n = 2; RUNX1::RUNX1T1, n = 2; and RUNX1mut, NUP98::NSD1, n = 1 each) or multiparameter flow cytometry (n = 7).

Written informed consent was obtained from all patients. All data obtained in this study involving human participants were collected in accordance with ethical standards of our institutional research committee (UCT, project-number: UCT-14-2022, SHN-1-2022) and with the 1964 Helsinki Declaration. Statistical analysis was performed using R version 4.3.3. The hazard ratio for CNS relapse was calculated using a cause-specific hazard model considering all-cause death a competing risk. Progression-free survival (PFS) and overall survival (OS) were calculated using Cox proportional hazard models and compared using a log-rank test.

We screened 273 patients who underwent the first HCT at our institution between January 2017 and December 2020 and retrospectively analyzed the data of 39 patients with FLT3-mutated AML who received intensive induction prior to transplant. Patient and treatment characteristics are detailed in Table 1. Of the 39 patients harboring a FLT3 mutation, 23 patients (58%) received a FLT3 inhibitor at some time during their treatment prior to transplant, mainly midostaurin.

Table 1 – Overview of analyzed patients with FLT3-ITD (n=34) and/or TKD-mutated AML (n=5) who were transplanted between 2017 and 2020 at our institution.

Patient characteristics (N=39)

N (%)

Age – median (range)

53 (20-75)

Sex

male

female

22 (56)

17 (44)

Mutations

FLT3-ITD / NPM1mut

FLT3-ITD / NPM1wt

FLT3-TKD

22 (56)

12 (30)

5 (12)

Genetic Risk Group (ELN2017)

favorable

intermediate

adverse

8 (21)

23 (59)

8 (21)

Genetic Risk Group (ELN2022)

favorable

intermediate

adverse

n/a

3 (8)

27 (69)

7 (18)

2 (5)

Donor type

matched-related

haploidentical

matched-unrelated

mismatched-unrelated

10 (26)

5 (13)

18 (46)

6 (15)

Conditioning regime

myeloablative

non-myeloablative

reduced-intensity

25 (64)

3 (8)

11 (28)

Remission status pre-HCT

CR1, MRD negative

CR1, MRD positive

CR2, MRD negative

CR2, MRD positive

Active disease

29 (74)

6 (15)

17 (44)

2 (5)

4 (10)

10 (26)

Remission status post-HCT

CR1, MRD negative

CR1, MRD positive

CR2, MRD negative

CR2, MRD positive

Active disease

37 (95)

21 (54)

9 (23)

5 (13)

2 (5)

At the time of HCT, 8 patients (21%) were MRD-negative, 21 (54%) in MRD-positive CR/CRi and 10 (26%) had active disease. 67% of patients (n = 26) received a myeloablative conditioning regimen. After HCT, defined as day 60–100 post-transplant, 37 patients (95%) were in CR/CRi with 26 (67%) also having MRD-negative disease. FLT3-targeted therapy after transplant was started prophylactically (n = 10) or pre-emptively (n = 10) at a median of 50 days (range, 28–346) post-HCT for a median duration of 13.5 months (1.4–32.2). Reasons for not receiving FLT3i treatment included HCT before maintenance therapy was routinely used in 2019 (n = 12), renal insufficiency (n = 1), FLT3-TKD only (n = 3) or early relapse (n = 2).

With a median follow-up of 44.9 months (range, 16.1–71.0), CNS relapse was observed more frequently in patients without CR/CRi pre-HCT (Fig. 1, Fig. 2A-B). After 1 and 2 years, cumulative incidence of CNS relapse was 20% (95% CI, 3–49) and 50% (16–77) in patients without CR/CRi compared to 0 of 29 (0%) in patients with CR/CRi. The cause-specific hazard ratio for CNS relapse was 24.5 (95% CI, 2.9-206.2; p = 0.003). CNS relapse occurred both as the first (n = 4) and later (n = 3) event of disease progression (Fig. 1).

Treatment of CNS relapse consisted of intrathecal chemotherapy (12 mg or 15 mg methotrexate, 40 mg cytarabine and 4 mg dexamethasone) in 6 of 7 patients (Fig. 1). Radiation therapy was administered in 5 patients with three patients receiving whole brain radiation and two spinal radiation. All patients were treated with donor lymphocyte infusions at some point after relapse.

PFS was shorter in patients not achieving CR/CRi prior to HCT with a median PFS of 11.4 months (95% CI, 3.5-not estimable [NE]). Median PFS was not reached in CR/CRi patients. HR for disease progression or death was 3.86 (95% CI, 1.58–9.39; p = 0.003; Fig. 2C). Accordingly, OS was shorter in patients without CR/CRi prior HCT with the median OS being 33.6 months (17.6-NE) vs. not reached. HR for death was 3.29 (1.15–9.46; p = 0.027; Fig. 2D).

Figure 2 – Competing risk analysis and survival outcomes

Panels A and B show the cumulative incidence of CNS relapse (panel A) considering all-cause mortality a competing risk (panel B). Panels C and D illustrate progression-free (C) and overall survival (D). CI denotes confidence interval, CR/CRi complete response with/without recovery, Cum. Cumulative, HCT hematopoietic stem cell transplantation, and HR hazard ratio.

This study confirms that patients with FLT3-mutated AML and active disease at the time of HCT have a high risk of CNS relapse and leukemic death. Overall 15 out of 39 patients with FLT3-mutated AML relapsed, seven of them with CNS disease.

In recent years, the incorporation of FLT3i into front-line treatment has continually improved the dismal prognosis of patients with FLT3-mutated AML and targeting FLT3 signaling with small molecule inhibitors has emerged as a promising therapeutic strategy prior to and after HCT as maintenance therapy. In two randomized trials, the strongest benefit from sorafenib maintenance was shown in patients with undetectable MRD pre-HCT as well as detectable MRD post-HCT. (5, 6) Gilteritinib as maintenance therapy following HCT was evaluated in the phase 3 BMT-CTN 1506 (MORPHO)-trial, resulting in a statistically significant improvement of relapse-free survival in patients with detectable MRD before and/or after HCT. (13) These studies indicate the importance of maintenance therapies in FLT3-mutated AML after HCT in patients who are not in molecular CR prior to and/or after HCT. In our study, two patients with CNS relapse after HCT responded to gilteritinib therapy, one in combination with intrathecal chemotherapy and one in combination with radiation of meningeal myeloid sarcoma. Both patients achieved MRD negative CR and are still alive. Our observation of intracranial activity of gilteritinib is also supported by previous case reports of durable CNS responses in patients with meningeal FLT3-mutated AML. (14, 15)

Another approach to prevent CNS relapse in FLT3-mutated AML may be switching to CNS directed induction therapy. In a subgroup analysis of the NCRI AML19 trial (ISRCTN78449203), which enrolled patients with newly diagnosed de novo or secondary AML, there was an OS benefit observed for FLAG-Ida + GO (fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, gemtuzumab ozogamicin) in patients with NPM1-mutated and FLT3-mutated AML (both FLT3-ITD and TKD). (16) Although there is no available data on the incidence of CNS relapse in the NCRI AML19 trial, the higher and more CNS-active single doses of cytarabine (2000 mg/m²) in FLAG-Ida, compared to DA (100 mg/m²), may provide better protection against CNS relapse. Another approach might be adding targeted therapies prior to transplant in FLT3-mutated patients to achieve complete remission. Among patients with relapsed or refractory FLT3-mutated AML included in the phase 3 ADMIRAL trial treatment with gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy. (17)

Although the findings of our study are limited by the small patient cohort, our results suggest that additional therapy might be considered for patients with active disease prior to transplant where relapse with CNS involvement seems to be common. Optimizing induction therapy, prophylactic intrathecal therapy, additional cranial irradiation, or closer monitoring may be considered to avoid CNS relapse.

Ethical approval: All data obtained in this study involving human participants were collected in accordance with ethical standards of our institutional research committee (UCT, project-number: UCT-14-2022, SHN-1-2022) and with the 1964 Helsinki Declaration

Funding: No funding was received for conducting this study.

Consent to participate: Informed consent was obtained from all individual participants included in the study.

Conflicts of Interest: KK received support for attending meetings from BeiGene (not related to this work). FA received support for attending meetings and speaker’s honoraria from AstraZeneca and consultant fees from IQVIA and AMGEN (not related to this work). FL received honoraria and consultant fees from Bristol Myers Squibb, Incyte, and Celgene and consultancy, honoraria and research funding from Novartis (not related to this work). GB received honoraria from BMS, Gilead, Jazz, Novartis and Otsuka and travel support from Gilead and Jazz (not related to this work).

Data Availability: Data will be made available upon reasonable request to the corresponding author.

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Competing interest reported. KK received support for attending meetings from BeiGene (not related to this work). FA received support for attending meetings and speaker’s honoraria from AstraZeneca and consultant fees from IQVIA and AMGEN (not related to this work). FL received honoraria and consultant fees from Bristol Myers Squibb, Incyte, and Celgene and consultancy, honoraria and research funding from Novartis (not related to this work). GB received honoraria from BMS, Gilead, Jazz, Novartis and Otsuka and travel support from Gilead and Jazz (not related to this work).

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Central nervous system relapse after allogeneic HCT in FLT3-mutated AML

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