Lenalidomide Combined to Azacitidine in Intermediate-2 or High Risk MDS With Del 5q
Lenalidomide Combined to Azacitidine in Intermediate-2 or High Risk MDS With Del 5q
Higher risk MDS with del(5q) carry very poor prognosis, but show some response to azacitidine
 and Lenalidomide as single agents . The combination of Lenalidomide and Azacytidine is
 currently tested in non del 5q MDS patients. Preliminary results have been recently presented
 at ASH meeting (Sekeres et al, 2007).

 Overall, the combination of Lenalidomide and Azacitidine is well-tolerated and early results
 suggest some efficacy in advanced MDS without del 5q.

 In this trial, we will combine Lenalidomide to Azacytidine in higher risk MDS with del (5q).

 Patients will receive azacitidine( 75mg/m2/day for 5 days every 28 days) combined to
 escalating doses of lenalidomide (starting at relatively low dose).

 For patients in hematological CR, PR, HI or marrow CR after cycle 2 or 4, it is mandatory to
 continue on Azacitidine + Lenalidomide as long as there is no unacceptable toxicity or overt
 progression, with the schedule that yielded response.

 In patient still responding after 52 weeks, the drug will continue to be supplied, and follow
 up until death will be continued in all patients.
Inclusion Criteria:

 1. age > ou = 18 years and < 75 years.

 2. must understand and voluntarily sign an informed consent form.

 3. patient considered ineligible for intensive chemotherapy due to age, cardiac
 contraindication to anthracyclines, comorbidities, previous failure of intensive
 chemotherapy, or patient willing to avoid intensive chemotherapy.

 4. must be able to adhere to the study visit schedule and other protocol requirements.

 5. prior thalidomide allowed.

 6. documented diagnosis of MDS (according to FAB definition, ie. with marrow blasts up to
 30%, or CMML with WBC < 13000/mm3 that meets IPSS criteria for intermediate-2 or
 high-risk disease.

 7. with an associated del 5q[31](the deleted chromosomal region must include 5q[31]),
 with or without additional cytogenetic abnormalities.

 8. female subjects of childbearing potential must:

 -  understand the study drug is expected to have a teratogenic risk.

 -  agree to have a medically supervised pregnancy test with a minimum sensitivity of
 25mIU/ml on the day of the study visit or in the 3 days prior to the study visit
 once the subject has been on effective contraception for at least weeks. This
 requirement also applies to women of childbearing potential who practice complete
 and continued abstinence. the test should ensure the subject is not pregnant when
 she starts treatment.

 -  agree to have a medically supervised pregnancy test every 4 weeks including 4
 weeks after the end of study treatment, except in the case of confirmed tubal
 sterilization. these pregnancy tests should be performed on the day of the study
 visit or in the 3 days prior to the study visit.

 this requirement also applies to women of childbearing potential who practice complete
 and continued abstinence.

 * agree to use, and to be able to comply with effective contraception without
 interruption, 4 weeks before starting study drug throughout the entire duration study
 drug therapy(including doses interruptions)and for 3 months after the end of the study
 drug therapy even if she has amenorrhea this applies unless the subject commits to
 absolute and continuous abstinence confirmed on a monthly basis, to avoid pregnancy
 for the duration of study.

 the following are effective methods of contraception:

 -  implant

 -  levonorgestrel-releasing intrauterine system(IUS)

 -  Medroxyprogesterone acetate depot, tubal sterilization.

 -  sexual intercourse with a vasectomised male partner only(vasectomised must be
 confirmed by two negative semen analyses), ovulation inhibitory progesterone-only
 pills(i.e.desogestrel).

 if not established on effective contraception, the female subject must be referred to
 an appropriately trained health care professional for contraceptive advice in order
 that contraception can be initiated.

 Because of the increased risk of venous thromboembolism in patients with multiple
 myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are
 not recommended. If a female subject is currently using combined oral contraception,
 the patient should switch to one of the effective methods listed above. The risk of
 venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral
 contraception. The efficacy of contraceptive steroids may be reduced during
 co-treatment with dexamethasone.

 Implants and levonorgestrel-releasing intrauterine systems are associated with an
 increased risk of infection at the time of insertion and irregular vaginal bleeding.
 Prophylactic antibiotics should be considered particularly in patients with
 neutropenia .

 Copper-releasing intrauterine devices are generally not recommended due to the
 potential risks of infection at the time of insertion and menstrual blood loss which
 may compromise patients with neutropenia or thrombocytopenia.

 -  Understand that even if she has amenorrhea, she must follow all the advice on
 effective contraception.

 -  She understands the potential consequences of pregnancy and the need to rapidly
 consult if there is a risk of pregnancy

 9. Male patients must :

 -  Agree the need for the use of a condom if engaged in sexual activity with a woman
 of childbearing potential. during the entire period of treatment, even if
 disruption of treatment and during 3 months after end of treatment

 -  Agree not to conceive during treatment and study drug therapy (including doses
 interruptions) and for 3 months after the end of the study drug therapy

 -  Agree not to donate semen during study drug therapy and for one week after end of
 study drug therapy.

 -  Agree to learn about the procedures for preservation of sperm., before starting
 treatment

 10. All subjects must :

 -  Agree to abstain from donating blood while taking study drug therapy and for one
 week following discontinuation of study drug therapy.

 -  Agree not to share study medication with another person and to return all unused
 study drug to the investigator.

 11. Signed informed consent prior to start of any study-specific procedures,

 12. Ability to participate to a clinical trial and adhere to study procedures.

 -  Criteria for women of non-childbearing potential :

 A female patient or a female partner of a male patient is considered to have childbearing
 potential unless she meets at least one of the following criteria:

 -  Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer
 therapy does not rule out childbearing potential)

 -  Premature ovarian failure confirmed by a specialist gynaecologist

 -  Previous bilateral salpingo-oophorectomy, or hysterectomy

 -  XY genotype, Turner syndrome, uterine agenesis.