Lenalidomide Active for Non 5q-Low Risk MDS

Abstract & Commentary

By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.

Synopsis: Lenalidomide is highly effective for low risk MDS associated with a deletion(5q). Raza and colleagues report on lenalidomide for low to intermediate-1 (int-1) risk MDS who were transfusion dependent but without a deletion(5q). Patients received 10 mg daily of lenalidomide either continuously or 21 out of 28 days. Grade 3 and 4 neutropenia and thrombocytopenia occurred in 25 and 20% respectively. Among the 214 patients, 43% responded of which 26% became transfusion independent and the hemoglobin exceeded 10 g/dL. Lenalidomide is an option for red blood cell transfusion dependent low risk MDS, even in patients without a 5q-deletion.

Source: Raza A, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other then deletion 5q. Blood. 2008;111:86-93.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by peripheral blood cytopenias, bone marrow hyperplasia, and a proclivity toward progression to acute myeloid leukemia. Prognostic scoring systems such as the International Prognostic Scoring System (IPSS) stratify prognosis and thus guide therapy.1 For those harboring high-risk IPSS scores, usually due to the presence of increased marrow myeloblasts and/or an adverse karyotype, a short progression to AML and death leads treatment to focus on disease reduction. Lower-risk MDS often manifests a smoldering course where anemia dominates the clinical picture. Anemia can lead to severe fatigue, red blood cell transfusion dependence, and transfusional iron overload. Lenalidomide is an oral thalidomide analog that has marked activity and FDA approval for low-risk MDS harboring a chromosome 5q interstitial deletion.2

In this trial, Raza and investigators report on lenalidomide for low-risk MDS without the 5q-syndrome. Patients had MDS with an IPSS of low or int-1-risk and required 2 units or more of red blood cells within the prior 8 weeks. Patients with baseline neutropenia (< 500/uL) or thrombocytopenia (<50,000/uL) were excluded because of the known cytopenias related to lenalidomide.

Among the 214 patients enrolled, the median age was 72 years and 65% required 2 or more red blood cell units per month at baseline. The majority had WHO subtypes of refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS). One hundred patients were treated at 10 mg daily of lenalidomide orally days 1-21 on a 28-day schedule. After protocol modification, 114 subsequent patients received lenalidomide 10 mg daily continuously.

Grade 3 or 4 neutropenia occurred in 25% and thrombocytopenia in 20%. Rash and pruritus were seen in 24 and 21%, respectively, although rarely reaching grade 3. Using the modified IWG 2000 response criteria, 43% responded to treatment with 26% of all patients treated achieving red blood cell transfusion independence (TI) and a hemoglobin > 10.0 g/dL. Among those achieving red blood cell transfusion independence (TI), the median time to TI was 4.8 weeks, 90% achieved this milestone by 16.9 weeks, the median duration of TI was 40 weeks, and in 36% (n = 20) TI lasted for greater then 1 year. Greater red blood cell dependence at baseline reduced the probability of responding. Only 47 patients had a clonal cytogenetic abnormality, of whom 4 had a complete cytogenetic response and 5 had a partial cytogenetic response. During treatment, only 2 of 27 patients with > 5% blasts had a 50% or greater reduction in marrow blasts.

Commentary

In this study, Raza and colleagues report reasonable activity of lenalidomide, as measured by a reduction in red blood cell transfusion dependence, in low-risk transfusion dependent MDS patients without the 5q- cytogenetic abnormality. Among the 214 patients enrolled, 43% met objective response criteria and 26% became transfusion independent (TI) and had hemoglobin > 10 g/dL. The median time to TI was only about 5 weeks. Most (90%) who achieved TI had done so by just over 4 months. Thus, one may need to wait 4 months before determining if lenalidomide is effective for a patient. The two dosing strategies of 10 mg per day for 21 of 28 days and continuous daily dosing had similar efficacy.

Toxicities were as expected with grade 3 or 4 neutropenia and thrombocytopenia occurring in 25% and 20% respectively. Patients could not have severe neutropenia or thrombocytopenia at baseline. Using lenalidomide in MDS patients will necessitate close monitoring for cytopenias, especially if used in those with baseline neutropenia or thrombocytopenia.

The results mirror the results the data reported in the initial studies of lenalidomide for MDS.

The results are interesting. On one hand, they are clearly less impressive than the activity in 5q- MDS with a 36% complete cytogenetic response rate and 67% achieving TI2,3 compared to a 9% cytogenetic response rate and 26% achieving TI in this study. Nevertheless, 5q- patients represent only a small subset of MDS patients and these results apply to a larger cohort.

Now the ultimate question arises how to sequence lenalidomide in MDS treatment as the therapeutic arsenal for MDS has grown to include ESA's, immunosuppression (particularly for HLA-DR 15 positivity), and hypomethylating agents (5-azacytadine and decitabine). One should always begin the process of hematopoietic cell transplant for the select patients who might be eligible. Lenalidomide obviously will continue to be the choice for deletion (5q) low-risk MDS. For patients with low risk MDS and a hemoglobin < 10 g/dL, a low transfusion burden, and a relatively low serum EPO level (ie, < 200 mU/mL or < 500 mU/mL), ESA therapy +/- G-CSF remains a reasonable therapy.4 Lenalidomide can now be considered an option for patients who are unlikely to respond or where ESA therapy has failed. Diligent monitoring for cytopenias is required. Controlled studies are needed comparing hypothemethylating agents and lenalidomide for transfusion dependent low-risk MDS.

References

1. Greenberg P, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088. Erratum in Blood 1998 Feb 1;91(3):1100.

2. List A, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549-557.

3. List A, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.

4. Hellstrom-Lindberg E, et al. Br J Haematol. 2003;120:1037-1046.