Several interesting studies related to the biology and treatment of MDS were reported at ASH 2006, which will be summarized below. 

Incidence of MDS in the United States

Rollinson et al. reviewed the SEER 2003 data regarding MDS in the United States.  They estimated the incidence of MDS to be about 14,650 cases.  There was male predominance (2:1).  The incidence of MDS was five times higher in patients age 80 years or older versus patients age 60 to 69 (36.3 versus 7.4 cases/100,000).  This is the first report of the incidence of MDS in the United States, an incidence similar to that reported from Europe.  With a median survival of about 3 years, the prevalence of MDS would be about 40,000 to 50,000 patients in the U.S.[1]

Importance of Cytogenetics in MDS 

Haase et al. reviewed the German-Austrian database in 2072 patients with MDS.  1202 patients received supportive care.  They divided the patients into 23 cytogenetic subgroups with 4 prognostic groups (Table 1).  

Table 1: Cytogenetics and Prognosis in MDS

Cytogenetic Category	Median Survival (mos)
9q-, 15q-,t(15q), 12p-, +21, 5q-	> 77
-X, normal, -Y, t(1q), t(7q), t(11q), -21	32 – 56
11q-, +8, +19, 7q-/-7, complex 3 abn	14 – 26
Complex > 3 abn, t(5q)	4.4 – 8.7

Patients in the 4 cytogenetic subgroups had estimated median survival ranges of more than 77 months versus 32, to 36 months versus 14, to 26 months versus fewer than 9 months.  This study should help refine the prognostic subsets in the commonly used International Prognostic Scoring System (IPSS).[2] 

In a second study by the same group, the authors reviewed the data in 2124 patients with MDS whose median survival time (MST) was 37 months.  Based on their analysis, they emphasized that the IPSS underestimated the poor prognostic significance of poor cytogenetic categories the IPSS score of which is only 1.0, but which predict for as poor an outcome as marrow blasts 21-30% (IPSS score 2.0).  This is illustrated in the Table 2 below.[3]

Table 2: Prognostic of Different Features in MDS 

Parameter	No	Change of MST from overall median (mos)
Blasts < 5%	609	+ 20.5
Good CG	768	+ 18
Blasts 5 - 10%	231	– 9.5
Int. CG	222	– 9.5
Blasts 11 - 20%	160	– 20
Poor CG	212	– 26
Blasts 21 - 30%	92	– 26

Growth Factors in MDS

In a study by Mundle et al., a meta-analysis compared the results of 9 studies using erythropoietin alpha (EPO, n=589) to 8 studies using the longer acting Aranesp® (darbepoetin alpha, DARB, n=387).[4] Erythroid response rates were according to the International Working Group criteria.  Endogenous EPO levels were higher in the EPO versus DARB studies (p=0.02).  The erythroid response rates were similar with EPO versus DARB overall (58 versus 59 percent) and by dose (standard dose response rates 48% with EPO versus 53% with DARB; high dose response rate 63% with EPO versus 70% with DARB).  However, the response rates with each drug were higher with the high dose versus standard dose treatment (EPO 63% versus 48%, p<0.001; DARB 71% versus 53%, p<0.001).

In a study by Jadersten, the investigators compared the outcome of patients with MDS from the Nordic studies which consistently gave EPO to patients with anemia and transfusion needs (n=123), to the Pavia studies in which no EPO was given (n=240).  In the Nordic studies, the erythroid response rate was 41%, and the median response duration was 23 months.  In a multivariate analysis of the total study group, survival was significantly better in patients receiving EPO if they had low RBC transfusion needs, i.e. less than 2 units of RBCs per month (hazard ratio .57, p=0.015).  There was no effect in patients with higher transfusion needs (p=0.36).  There also was no impact of using EPO with or without GCSF on AML transformation.  This study suggests that EPO use may reduce mortality in MDS with low transfusion needs, perhaps by reducing iron overload and its related organ damage complications.[5] 

This brings about the issue of iron overload and iron chelation therapy in MDS, two quite controversial issues. 

Takatoku et al. reviewed their experience in 292 patients with MDS (52%) or other disorders.  These patients had a median disease duration of 32 months; 80% had received more or equal 40 units of packed RBCs.  Desferioxamine (DFO) was given to 46% of patients.  Abnormal cardiac functions were found in 14 of 46 patients evaluated (22%) and liver function abnormalities in 11 of 15 patients evaluated.  Among 75 deaths, congestive heart failure was significant in 24% and hepatic failure in 7%.  More patients died with ferritin levels more or equal to 1000 ng per ml than patients with lower ferritin levels (49% versus 1%).  Continuous DFO therapy improved ferritin levels, liver function abnormalities, and hyperglycemia.[6] 

In another study by Leitch et al., 178 patients with MDS were evaluated for the benefit of iron chelation therapy.  There median age was 69 years.  IPSS low or intermediate 1 risk disease was noted in 99 of 133 evaluable patients.  High serum ferritin levels more than 2000 ng/ml were present in 28, iron overload in 22, congestive heart failure in 5, and liver-endocrine abnormalities in 22.   Eighteen patients received iron chelation therapy in the form of DFO, .5 to 3 grams subcutaneously by continuous infusion 5 days a week.  A multivariate analysis for survival identified IPSS score (p=0.008) and iron chelation therapy (favorable; p=0.02) to be important independent prognostic factors.  Among patients with IPSS low – intermediate 1 risk, the median survival was more than 160 months with iron chelation therapy versus 40 months without iron chelation therapy (p=0.03).[7] 

Update of Revlimid ® (Lenalidomide) in MDS 

Revlimid is now FDA approved for the treatment of low risk MDS, transfusion dependence, with deletion 5q abnormality and reasonable platelet counts.  At the ASH meeting the two pivotal studies of Revlimid in lower risk MDS, transfusion dependence, with and without deletion 5q, were updated.  List et al. updated the results of 148 patients with low risk MDS, deletion 5q, transfusion dependence, treated with Revlimid 10 mg orally daily for 3 weeks every month or continuously.[8] Sixty-seven percent of patients achieved red cell transfusion independence.  The median hemoglobin increase was 5.4 grams per dl.  The median response duration was 116 weeks.  Thirty-seven of 85 evaluable patients (44%; 25% of total) achieved a complete cytogenetic response.  Grade 3-4 neutropenia was noted in 59% and thrombocytopenia in 50%; treatment discontinuation was necessary in 9% of patients.  Raza et al. reported on 214 patients with lower risk MDS and transfusion dependent anemia. [9] IPSS low-intermediate 1 was noted in 78%.  They received Revlimid 10 mg orally daily for 3 weeks every month or continuously.  Red cell transfusion independence was noted in 56 patients (26%) and red cell hematologic improvement in 92 patients (43%).  The median time to response was 4 weeks; the median hemoglobin increase was 3.2 grams per dl.  The median response duration was 43 weeks.  Nine of 47 patients (19%) with cytogenetic abnormalities had a reduction of the chromosomal abnormality:  4 (8%) achieved a complete cytogenetic response.  Grade 3-4 myelosuppression was noted in 20-25%. 

The question is how do these results compare with other therapies preceding the Revlimid era?  Kelaidi et al. reviewed the results of EPO + GCSF, and of Thalomid® (thalidomide), in patients with MDS with or without deletion 5q.  Among patients with deletion 5q, the erythroid response rate to EPO was 46%, and the median response duration was 47 months.  The response rate with Thalomid was only 38%.  In patients without deletion 5q, the erythroid response rate to EPO was 64%, lasting for a median duration of 24 months. Response rate to Thalomid was 29%.[10] These comparative results suggest that Revlimid shows better and more durable responses in low risk MDS with deletion 5q, while EPO is associated with better and more durable responses in patients without deletion 5q.

Update of Hypomethylating Agents in MDS

Several studies reported on the results of Vidaza® (azacitidine) and Dacogen® (decitabine) in MDS.  In the French studies by Fabre et al., 90 patients with MDS received Vidaza 75 mg /m2 subcutaneously daily x 7 every 4 weeks.[11] Among 61 evaluable patients, 10 (16%) achieved CR, 15 (25%) had PR, and 13 (21%) showed hematologic improvement, for an overall response rate of 62%.  The median survival was 7 months. 

Lyons et al. tested three schedules of Vidaza:  1)  75mg /m2 daily x 5, with 2 days on, and 2 more days (525 mg/m2/course); 2) 50 mg/m2 daily x 5, 2 days off, 5 more days (500 mg/m2/course); 3) 75 mg/m2 daily x 5 (375 mg/m2/course).   Hematologic response rates were similar across the 3 schedules (52% to 65%).  The erythroid hematologic improvement rates were 42% to 46%, platelet response rates 16% to 23%, and neutrophil response rates 11% to 16%.[12] 

Vidaza was also combined with MS275 (histone deacetylase inhibitor).  Gore et al. gave Vidaza 30-50 mg/m2 daily x 10 with MS275 2-8 mg/m2 on day 3 and 10, every 4 weeks, to 31 patients (13 MDS, 4 CMML, 14 AML).[13] They observed 12 responses (39%), including 2 CR, 4 PR, and 6 hematologic improvements.  The median number of courses to a response was 2, and to best response 4.

Rosetti et al. evaluated the effect of adding GCSF to Vidaza therapy on response.  GCSF is a standard of care in MDS, but the IWG response criteria do not allow for concomitant use of growth factors.  In a study of 86 patients with MDS treated with Vidaza alone (n=37) or Vidaza with EPO + GCSF (n=49).  The overall hematologic improvement rate was 51% with Vidaza alone versus 84% with Vidaza + GCSF (p=0.003).  The erythroid HI response rates were 37% versus 77% (p=0.001); the platelet HI response rates were 47% versus 72% (p=0.04).  Surprisingly the neutrophil HI response rates were 67% versus 71% (p not significant).[14] This study suggests that adding growth factor support to hypomethylating agent therapy may improve the results in MDS. 

Jabbour et al. reported on 115 patients with higher risk MDS treated with Dacogen.  Their outcome was compared to matched historical patients treated with intensive chemotherapy (n=115), as well as with the total historical experience of patients treated with intensive chemotherapy from 1995-2005 (n=376).  The CR rates were similar with Dacogen versus intensive chemotherapy (43% versus 46%).  However, the mortality rates at 6 weeks (3% versus 12%) and at 3 months (7% versus 22%) were better with Dacogen.  The median survivals were also better with Dacogen (22 months versus 11 months) as were the survival rates at 2 years (47% versus 25%).  A multivariate analysis of all 491 patients treated selected Dacogen therapy as a favorable prognostic factor (hazard ratio .76; p=0.002).[15]

A study of Dacogen given at 20 mg/m2 daily x 5 every month in patients with MDS and failure on Vidaza therapy resulted in 3 CRs and 2 hematologic improvements among 14 patients treated.  The median response duration was 5.3 months.[16]

Finally, two studies of Dacogen in CMML by the M. D. Anderson Cancer Center Group and Wijermans et al. show favorable activity.[17],[18] In the study from M. D. Anderson Cancer Center, 19 patients received Dacogen 100 mg/m2 per course:  11 (58%) achieved a CR and 13 (69%) had some objective response.  In the study by Wijermans et al., Dacogen was given at 145 mg/m2 by continuous infusion over 3 days every 6-8 weeks to 28 patients:  4 (14%) achieved CR and 11 (39%) had an objective response.

Other Studies in MDS

GX15-070 is a small molecule pan-Bcl 2 inhibitor.  It was given at 7-40 mg/m2 over 24 hours every 2 weeks to 14 patients (8 MDS, 5 AML, 1 CLL).  Hematologic improvements were observed in 3 out of 8 patients with MDS.[19]

Faderl et al. treated patients with MDS with oral Clolar® (clofarabine) 40 mg/m2 daily x 5 every month (n=6) or intravenous Clolar 15 or 30 mg/m2 IV daily x 5 every month (n=13).  Responses were observed in 2 of 6 patients with oral Clolar (33%) and in 8 of 13 patients with IV Clolar (61.5%).[20] 

Summary: How Does This New Information in MDS Affect Our Practice in 2007?

The above studies:

• Highlight the importance of cytogenetic studies in MDS, both for prognosis and for therapy (e.g. use of Revlimid in low risk MDS with deletion 5q).
• Establish the role of growth factors in improving quality of life, and perhaps survival, in lower risk MDS, as well as in possibly improving response rates with hypomethylating agents.
• Emphasize the significance of iron overload and the possible need for iron chelation therapy.
• Confirm the role of Revlimid as standard therapy in lower risk MDS, red cell transfusion dependence, and deletion 5q.  The role of Revlimid in other MDS settings remains investigational.
• Confirm the value of hypomethylating agents as a new standard of care in MDS and CMML.

References

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[1]Rollinson D, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER program. Blood. 2006;108:77a, abstract 247.