Ruxolitinib is effective in the treatment of a patient with refractory T‐ALL

Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare, aggressive T‐cell malignancy. Chemotherapy alone cures only 25‐45% of the cases, thus, novel treatment agents and strategies are urgently needed. We assessed the efficacy of ruxolitinib in a patient with a cutaneous relapse after allogeneic blood cell transplantation of a refractory T‐ALL with a Janus kinase 3 (JAK3) mutation. In this case report, we were able to show the potential benefit of the JAK inhibitor ruxolitinib in JAK3‐mutated refractory T‐ALL and emphasize the importance of integrating molecular markers in current treatment decision making for patients with T‐ALL.

a KMT2A rearrangement, other than AFF1. According to the WHO 2016 Classification, the case was categorized as precursor T-cell acute lymphoblastic leukemia (T-ALL). Specific treatment following the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) 07/03 protocol was initiated [1]. The patient reached complete hematological remission (hCR) but remained positive for measurable residual disease (MRD) (real-time quantitative polymerase chain reaction (qRT-PCR), detection limit of 1 × 10 −5 for both markers). According to protocol, after first consolidation, the patient proceeded to human leukocyte antigen matched related donor allogeneic hematopoietic stem cell transplantation, achieved molecular complete remission and complete resolution of the skin lesions.
In the following years, the patient suffered a series of cutaneous relapses while maintaining complete donor chimerism and MRD negativity until May 2018. After that, the MRD results turned positive at the above-mentioned detection level while maintaining hCR. Cutaneous relapses were treated as shown in Table 1. The last cutaneous relapse occurred on the right leg ( Figure 1A) in March 2020, as confirmed by histology and immunohistochemistry ( Figures 1B and 1C).   [3,4], the decision was made to pursue therapy with ruxolitinib in combination with tofacitinib.
Due to major contraindications to tofacitinib in our patient (deep vein thrombosis of the jugular and subclavian vein and heart failure NYHA III), the salvage therapy with ruxolitinib 10 mg twice daily was initiated.
An interim examination on day 15 revealed moderate anemia (Hb 10.5 g/L) with otherwise no relevant side effects from the therapy. The cutaneous lesions completely dissolved ( Figure 1D), donor chimerism was 100%, but MRD remained positive at the detection limit (1 × 10 −5 ). At the second staging on day 50, we could confirm a complete remission of the skin lesions. No further treatment related toxicities were encountered. Ruxolitinib was discontinued after 5 months due to a cutaneous relapse and increasing MRD in peripheral blood and BM.
A therapy with decitabine and venetoclax was started and soon after, due to lack of response, multiple infectious complications and relevant clinical deterioration, treatment deescalation was discussed with the patient and a best supportive care therapy was pursued.

DISCUSSION
T-ALL is a rare, aggressive T-cell malignancy.  The JAK/STAT signaling pathway plays an essential role in normal hematopoiesis. JAK2 helps in the maintenance of hematopoietic stem cells and various stages of myelopoiesis [8], whereas JAK1 cooperates with JAK3 for lymphopoiesis. JAK3 mutations have been reported in 10-16% of T-ALL patients, with JAK3 M511I being the most frequently identified mutation [9]. JAK3 mutations have been reported to be dependent on binding to the common γ chain of cytokine receptor complexes [10].
Targeted therapy with tofacitinib, a pan-JAK inhibitor, in combination with ruxolitinib was suggested based on the sequencing results.
This was supported by previous preclinical data regarding its effectiveness of targeting JAK3 mutations as well as a successful therapy with tofacitinib described in a single-patient case report with T-ALL and a JAK3 mutation [11,12]. Accordingly, tofacitinib, combined with ruxolitinib, has an enhanced potency in vitro in other disease models aiming to inhibit the IL2RG-JAK1-JAK3-STAT5B signaling pathway [13]. As JAK3 mutants are dependent on JAK1 signaling for their cellular transformation, it is possible to use both JAK1/JAK2 and JAK3selective inhibitors in JAK3 mutation-positive leukemia [11]. However, as previously mentioned, due to existing contraindications to tofacitinib, single-agent ruxolitinib was initiated.
As seen in previous publications in T-ALL murine xenograft models, the patient showed a remarkable response of the skin lesions with ruxolitinib, independently of the presence of JAK1 or JAK2 mutations. 14 Inline, JAK3 M511I was found to obtain an increased JAK/STAT signaling by acquiring an additional mutation in the pseudokinase domain, which was also present in our patient. 15 Since our patient had complete donor chimerism, we assumed that the graft versus leukemia effect was sufficient to maintain an hCR in the BM but not to prevent the skin relapse. Leukemic cells were able to evade immune surveillance and migrate into peripheral tissues; however, single-agent ruxolitinib was able to induce complete remission of the extramedullary relapse in our case.
Our results illustrate the potential benefit of the JAK inhibitor rux-