Azacitidine, Lenalidomide and DLI as Salvage Therapy for MDS, CMML and sAML Relapsing After Allo-HSCT

Phase-II Trial to Assess the Efficacy and Safety of Lenalidomide in Addition to 5-Azacitidine and Donor Lymphocyte Infusions (DLI) for the Treatment of Patients With MDS, CMML or AML Who Relapse After Allogeneic Stem Cell Transplantation

This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate the safety and feasibility of the addition of Lenalidomide (investigational drug) to the standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts, formerly RAEB-T) after allo-SCT. The starting dose of Lenalidomid is 2.5 mg per day for 21 days with a 7 day rest. The study incorporates 2 interim safety analyses after 10 and 20 patients in order to find the optimal and safe dose of Lenalidomide.

This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate the safety and feasibility of the addition of Lenalidomide (investigational drug) to the standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts, formerly RAEB-T) after allo-SCT.

Study Design:

• prospective, open-label, single arm, multicenter phase-II trial
• total patients sample size: 50 patients
• number of trial sites: 6 all located in Germany and members of the EBMT Patients will be included at the time of relapse after first allo-SCT. Starting on day 1 all patients will receive Azacitidine 75 mg/m2/d for 7 days every 28 days for up to 8 cycles. DLIs will be given after cycle 4, 6 and 8. Lenalidomide will be also started on day 1 for 21 days every 28 days for a maximum of 8 cycles. The concomitant administration of Aza and Lenalidomide will be used since safety and efficacy of this schedule has been demonstrated.

Azacitidine and DLI represent a standard of care in this setting and are therefore not considered as investigational. As 5-Azacytidine is given in-label, treatment may be continued beyond 8 cycles. Additional DLIs may be given according to the investigators choice. However, to avoid severe GvHD it is recommended to give at least one more cycle 5-Azacytidine after additional DLIs.

The study incorporates a dose escalating schedule for Lenalidomide and two safety interim analyses. A first interim analysis will be performed as soon as 10 patients have been treated with Lenalidomide at a dose of 2.5mg/day If no dose limiting toxicity is observed in this cohort the next cohort of 10 patients will be treated with 5 mg per day for 21 days starting on day 1. If dose limiting toxicity occurs the study will be closed. A second interim analysis will be performed as soon as 10 patients have been treated with Lenalidomide at a dose of 5mg/day and the 10th patient of this cohort has either completed 4 cycles or has discontinued treatment whichever occurs first. If no dose limiting toxicity is observed in this cohort, the dose of 5 mg per day for 21 days starting on day 1 will be chosen and the remaining patients will be treated with this dose of Lenalidomide. If dose limiting toxicity occurs in patients treated with 5mg per day the remaining patients will be treated with Lenalidomide at a dose of 2.5mg/day. A total number of 50 patients will be treated.

Independent of the dose level, Lenalidomide will be stopped individually in the case of GvHD ≥ grade II.

Inclusion Criteria:

• First relapse of de novo or therapy-related MDS, CMML or AML according to WHO classification (revised version 2016) without FLT3 mutation and without known IDH mutation after first allo-SCT (related or unrelated donor with < 2 HLA mismatches)
• Possibility of DLI (no cord blood, no haploidentical donor)
• no previous therapy for relapse after allo-SCT
• ECOG performance status ≤ 2 at study entry
• no active GvHD treated with systemic immunosuppression within 4 weeks before inclusion
• no uncontrolled infection at inclusion
• Understand and voluntarily sign an informed consent form.
• Age 18 years at the time of signing the informed consent form.
• Able to adhere to the study visit schedule and other protocol requirements.
• All females must acknowledge to have understood the hazards and necessary precautions associated with the use of lenalidomide

Exclusion Criteria:

• Relapse after second allogeneic Transplantation

• AML with FLT3 mutation (ITD or TKD)

• AML with known IDH mutation (IDH1 or IDH2)

• Any previous therapy (chemotherapy, radiation or investigational drugs) administered as therapy for relapse after allo-SCT

• previous transplantation with cord blood, an haploidentical donor or a related/unrelated donor with

  ≥2 HLA mismatches

• Active GvHD requiring systemic immunosuppression within the last 4 weeks

• Uncontrolled infection

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.

• Pregnant or lactating females

• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

• Impaired renal function (GFR < 20 ml/min)

• Impaired hepatic function

• Known hypersensitivity to thalidomide, lenalidomide or any components of the treatment

• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.

• Concurrent use of other anti-cancer agents or treatments.

• Known positive for HIV or infectious hepatitis, type A, B or C.

• Neuropathy ≥ grade 2

• Prior history of malignancy other than MDS or AML (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years

• Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study