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American Society of Hematology Meeting Highlights

OBTN, February 2008, Volume 2, Issue 2

The American Society of Hematology (ASH) held its 49th AnnualMeeting at the Georgia World Congress Center in Atlanta in December. The following reports provide summary coverage of meeting highlights,primarily focusing upon notable research breakthroughs relatingto hematological malignancies.

49th Annual Meeting of the American Society of Hematology

Focus of hematological malignancies and notable research

The American Society of Hematology (ASH) held its 49th Annual Meeting at the Georgia World Congress Center in Atlanta in December. The Society's annual meeting provides a forum for hematologists from around the world to discuss critical issues in hematology.

Roughly 20,600 clinicians, scientists, and other hematology professionals hailing from over 100 countries attended the four-day meeting, which consists of educational programs and scientific sessions that address a wide range of issues relating to and covering the entire spectrum of hematological disorders.

In addition, the annual meeting features oral and poster presentations, chosen by peer-reviewers from abstracts submitted prior to the meeting, that feature the latest breaking developments in scientific research. For the 2007 meeting, 3,745 abstracts from 46 countries were accepted for presentation.

Mitchell Weiss, MD, PhD, Children’s Hospital of Philadelphia, Pennsylvania, and Scientific Co-Chair of ASH 2007, summarized its value in the following terms: “If you’re a practicing hematologist/oncologist, ASH is a very important meeting covering diverse topics. The educational and scientific sessions provide overviews of what’s hot in the field. So it’s a good place for clinicians to brush up the latest, newest emerging concepts that they might not see all the time. One can find out what the state of the art research is that will be coming into clinical practice five years from now. ASH offers a very comprehensive global view, from practical, clinical issues to cutting-edge research. Everything is important (in terms of) current clinical practice, clinical practice alterations, and things that are going to become clinical practice.”

The following highlights provide summary coverage of meeting highlights, primarily focusing upon notable research breakthroughs relating to hematological malignancies.

%u25BA Advances in Multiple Myeloma

Second in prevalence only to non-Hodgkin’s lymphoma, multiple myeloma (MM) is one of the most common hematologic malignancies in the United States. This severe form of bone marrow cancer is also one of the most

difficult to treat. Traditionally, MM outcomes have been poor. Survival rates for MM have not been promising: most patients die within two to three years after diagnosis. In 2007, an estimated 10,790 fatalities were attributed to the disease in the United States. However, over the past decade, survival rates have risen dramatically. Recent analyses delivered by numerous presenters at the 49th Annual American Society of Hematology meeting suggest that this trend may be attributed to new types of drugs, new treatment combinations and aggressive therapeutic interventions such as stem—cell transplantation (SCT).

Bortezomib-Melphalan-Prednisone Associated with Improved Efficacy Endpoints Compared With Melphalan-Prednisone in Newly Diagnosed Multiple Myeloma

Jesus San-Miguel, MD, Hematology Department Head, University Hospital of Salamanca, Salamanca, Spain, presented results from a 682-patient, randomized, Phase III trial comparing bortezomib (Velcade)-melphalan (Alkeran)-prednisone (Meticorten) (BMP) versus melphalan-prednisone (MP) in the treatment of patients with newly diagnosed MM who were ineligible to receive SCT.

Patients in the BMP arm of the study received bortezomib at 1.3 mg/m2 twice weekly in weeks one, two, four and five for four six-week cycles (eight doses per cycle), followed by once weekly on weeks one, two, four and five for five six- week cycles (four doses per cycle) in combination with melphalan at 9 mg/m2 and prednisone at 60 mg/m2 once daily on days 1 through 4 of each cycle. Patients in the MP arm received nine six-week cycles of MP once daily on days 1 through 4. For both groups, treatment continued for a maximum of 54 weeks (52 vials) with a median number of 46 weeks (44 vials) reported in the trial. The safety profile of BMP was as expected, based on the known safety profile of each of the three individual agents in the combination. Adverse events included neutropenia, thrombocytopenia, anemia and peripheral neuropathy. Discontinuation because of adverse events was low and similar in both arms.

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Responses were evaluated by the commonly used M-protein levels measured in serum or urine by a centralized laboratory as well as the most stringent European Group for Blood and Marrow Transplantation (EBMT) criteria. Key findings reported by Dr. San-Miguel included: an immunofixation-negative complete remission (CR) rate of 35% in the BMP arm compared with 5% with MP ( < 0.000001); a CR rate of 30% in the BMP arm compared with 4% with MP; a 24-month median duration of response for patients with CR in the BMP arm compared with 13 months in the MP arm; a 24-month time-to-disease progression (TTP) in the BMP arm, compared with 17 months with MP (= 0.0000001); and a statistically significant demonstration of overall survival associated with the BMP arm (a 40% reduction in risk of death (= 0.0078) was observed in the patient cohort undergoing BMP therapy).

According to researchers, the BMP arm of the clinical trial achieved significant improvement across all efficacy endpoints that were analyzed, most notably CR and long-term survival. Commenting on the results, Dr. San Miguel, the trial’s principal investigator, stated, "The goal of therapy is long-term survival and complete remission is a well-known indicator for survival. Data from this rigorously controlled trial clearly show that Velcade-based therapy should be a standard of care for previously untreated patients, who are not able to receive stem-cell transplantation."

Bortezomib-Thalidomide-Dexamethasone Yields Superior Response Compared With Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma

Michele Cavo, MD, Seragnoli Institute of Hematology, University of Bologna, Bologna, Italy, presented the results of a multicenter, randomized Phase III trial comparing a combined regimen of bortezomib (Velcade)-thalidomide (Thalomid)-dexamethasone (Decadron) (BTD) with thalidomide-dexamethasone (TD) combination therapy, incorporated into autologous stem-cell transplantation (ASCT) for newly diagnosed multiple myeloma.

In the trial, initiated in May 2006 by the Italian Myeloma Network (GIMEMA), both BTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan (Alkeran) 200 mg/m2. In both the BTD arm (arm A) and TD arm (arm B) of the study, induction therapy consisted of three 21-day courses of therapy (totaling 63 days).

The primary end point of the study was complete response (CR) [either immunofixation-negative CR or immunofixation-positive (nCR)] to induction therapy. Secondary study end points included CR nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned, to be performed after one year from study initiation, to assess efficacy and toxicity of induction therapy.

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As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive BTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR nCR to BTD was 38% versus 7% to TD (< 0.001) 60% of patients in BTD arm and 25% of patients in the control group attained at least a very good partial response ( <0.001). Patients who failed at least a partial response to BTD were signifi- cantly less than those who failed on TD (7% versus 21%, respectively; = 0.004).

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Adverse events were similar in both arms, with the exception of (grade 3 or higher) skin rash (6.5% in BTD arm versus 1% in TD arm; = 0.04). Treatment discontinuation resulting from adverse events was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase.

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A subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR nCR to melphalan was significantly higher in the BTD arm than in the control group (= 0.02 for CR comparison and = 0.05 for CR nCR comparison between the two treatment arms).

Preliminary analysis of this study provides demonstration that BTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR nCR rate compared with TD both before ASCT and after the first autologous transplantation with melphalan.

Principal trial investigator Dr. Cavo commented, "This Velcade-based induction regimen achieved a fourfold increase in the complete remission rate. Complete remission is widely recognized as a predictor for long-term survival. These exciting results demonstrated that adding Velcade to the standard induction therapy prior to stem cell transplantation improves the response rate dramatically."

Lenalidomide Plus Low-Dose Dexamethasone Demonstrates Superior Overall Survival Compared With Lenalidomide Plus High-Dose Dexamethasone

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S. Vincent Rajkumar, MD, Mayo Clinic, Rochester, Minnesota, reported the results of a randomized trial comparing lenalidomide (Revlimid) plus high-dose dexamethasone (Decadron) combination therapy with lenalidomide plus low-dose dexamethasone in patients with newly diagnosed multiple myeloma. Findings, drawn from a second preplanned interim analysis, indicated that overall survival was significantly superior in the subject cohort that received low-dose dexamethasone combination therapy (< 0.001).

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One-year survival rates observed in patients undergoing lenalidomide plus low-dose dexamethasone were 96% (compared with 87% survival in patient receiving lenalidomide plus high-dose dexamethasone). Survival rates after 18 months yielded similar results: patients taking lenalidomide plus low-dose dexamethasone were more likely to survive than their high-dose dexamethasone counterparts (survival rates of 91% and 80% were observed, respectively). The low-dose dexamethasone combination maintained its favorable survival rate across the span of patient age groups. Differences in favor of the low-dose dexamethasone cohort were seen both in patients under the age of 65 (97% versus 92% at one year, = 0.022) and in patients over the age of 65 (94% versus 83% at one year, = 0.002).

In addition, the low-dose dexamethasone combination was associated with decreased mortality. Of the 61 patients who perished over the duration of the study period, 42 were in the high-dose dexamethasone arm. The higher mortality incidence evidenced in the high-dose dexamethasone cohort was attributed to disease progression and increased toxicity.

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Patients who underwent lenalidomide plus high-dose dexamethasone therapy experienced a markedly higher rate of serious adverse events, including deep vein thrombosis/pulmonary embolism (DVT/PE) (25% versus 9%, < 0.001), infections (16% versus 6%, P < 0.001), grade 3 or higher nonhematologic events (49% versus 32%, < 0.001), grade 4 or higher nonhematologic events (20% versus 9%, < 0.001), and death in the first 4 months (5% versus 0.5%,

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= 0.006).

This study demonstrated that in patients with newly diagnosed multiple myeloma, lenalidomide plus low-dose dexamethasone combination therapy, as compared with lenalidomide plus high-dose dexamethasone combination therapy, is associated with superior overall survival, decreased toxicity, and decreased mortality.

“This is a major advance and gives researchers a new direction to explore—that more is not necessarily better,” commented Dr. Rajkumar.

Pegylated Liposomal Doxorubicin in Combination With Bortezomib May Provide an Advantage for High-Risk Patients Relapsing Within 12 Months of Stem-Cell Transplant

Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, Minnesota, presented results of a retrospective analysis of a large, phase III study (DOXIL-MMY3001) (Orlowski et al. JCO 2007), which demonstrated that the combination of pegylated liposomal doxorubicin (Doxil) (PLD) plus bortezomib (Velcade)(B) improved time to progression (TTP), compared with B monotherapy, in patients with multiple myeloma (MM) who relapse within 12 months of autologous stem-cell transplantation (ASCT).

The present analysis examined the 12-month post-randomization survival of 646 patients who had early (less than 12 mo) versus late (12 mo or later) relapse following ASCT, as well as the effect of PLD B versus B alone in patients who had relapsed early.

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Of the 359 patients who had previously received stem-cell transplant, 114 (32%) relapsed within 12 months. The median age, gender distribution, time from diagnosis, trial enrollment, measures of disease burden (M-Protein levels and B2M) and renal function were comparable between the early- and late-relapse groups. There was no difference in overall response rates [complete partial response (CR PR)] or very good partial response (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early versus late relapse groups (hazard ratio = 0.94). Twelve-month survival from randomization was significantly lower in the early relapse group as compared with late relapse (83% versus 92% respectively, = 0.009).

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However, within the early-relapse group, the 12-month post-randomization survival rate was significantly superior following treatment with PLD B as compared with B alone [52 of 56 patients (93%) versus 43 of 58 patients (74%) respectively, = 0.01]. (Patients received intravenous B, 1.3 mg/m2 on days 1,4,8 and 11 of every 21-day cycle with or without PLD, 30 mg/m2 on day 4.) Correspondingly, TTP was better in this group with PLD B versus B alone (276 days versus 205 days respectively, = 0.13). Overall, the toxicity profiles of the combination and B alone were comparable regardless of early or late relapse following ASCT.

According to the researchers, results demonstrate that PLD B may provide an important therapeutic advantage for high-risk MM patients who experience early relapse following ASCT.

Safety and Efficacy of Lenalidomide, Bortezomib, and Dexamethasone as Front- Line Therapy for Multiple Myeloma

Paul Richardson, MD, Dana- Farber Cancer Institute, Boston, presented preliminary results from a Phase I/II study designed to determine the maximum tolerated dose (MTD), and assess the safety and efficacy of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron) as combination therapy in newly diagnosed multiple myeloma (MM) patients.

Patients received lenalidomide 15—25 mg on days 1–14, bortezomib 1.0–1.3 mg/m2 on days 1, 4, 8, 11, and dexamethasone 40/20 mg (cycles 1—4/5–8) on days 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-day cycles, initially at four planned dose levels (lenalidomide/bortezomib: 15/1.0, 15/1.3, 20/1.3, and 25/1.3).

Dose escalation proceeded depending on dose-limiting toxicities (DLTs). Based on safety data, the maximum planned dose level (4M) was added with a reduced dexamethasone starting dose (lenalidomide/bortezomib 25/1.3, dex- amethasone 20 mg in all cycles). Patients with Grade 2 or higher peripheral neuropathy (PNY) were excluded.

Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform criteria. Patients with complete response—either immunofixation negative (CR) or immunofixation positive (nCR), very good partial response (VGPR) or partial response (PR) could proceed to autologous stem-cell transplantation (ASCT) after four or more cycles.

To date, 33 patients (median age 56 years, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled in dose levels 1—4 and at the maximum planned dose level (4M), respectively, including 10 patients enrolled at the maximum planned dose level (4M). Patients have received a median of five cycles; nine patients have completed all eight cycles. Two DLTs of Grade 3 hyperglycemia caused by high-dose dexamethasone were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for lenalidomide in nine pts, bortezomib in seven patients, and dexamethasone in 17 patients, with three dose reductions having occurred in dose level 4M.

Reported toxicities have been manageable. Only 1 Grade 4 toxicity (thrombocytopenia) has been reported, plus 1 Grade 3 deep venous thrombosis (DVT) (reversed with low molecular-weight heparin (LMWH) (Fragmin)), and no Grade 3 or higher PNY has been seen. The response rate across all dose cohorts (CR/nCR VGPR PR: subject to confirmation) is currently 89% in 25/28 evaluable patients, including 35% CR/nCR/VGPR.

After median follow-up of three months, median duration of response, TTP, progression-free survival, and overall survival have not been reached; all responders except one remain in remission, with two patients proceeding to ASCT.

Preliminary results of the study demonstrated the combination of lenalidomide/bortezomib/ dexamethasone is very active and well tolerated in newly diagnosed MM patients. The maximum planned dose has been reached at lenalidomide 25 mg, bortezomib 1.3 mg/m2, and dexamethasone 20 mg, with Phase 1 enrollment now complete using the lower dose of dexmethasone. Enrollment to the Phase 2 component is ongoing.

%u25BA Advances in Leukemia

Together, the multiple diseases that encompass leukemia—the four major types of which are acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML)—represent the most common form of blood cancer. Roughly $2.6 billion is spent each year in the United States on leukemia treatment. Despite this abundance of resources, leukemia incidence and mortality rates have remained relatively unchanged for more than the past two decades. At the most recent ASH annual conference, however, researchers sounded a hopeful tone, citing numerous examples of diagnostic and therapeutic progress.

According to Richard A. Larson, MD, University of Chicago, and moderator of an ASH press conference on 2007 research findings, “Every year, scientists are continually making advances in learning more about what causes normal bone marrow cells to become cancerous on the genetic level. Through this cutting edge research, we are finding more effective combination therapies and developing new targeted cancer agents that help extend the lives of our patients with leukemia. Research presented at this year’s meeting focuses on many of these innovative treatment advances.”

One of the topics that generated significant interest and attention at ASH 2007 was imatinib (Gleevec) therapy and the emerging, increasingly viable niche of replacement therapies for imatinib in cases where patients demonstrate therapeutic resistance or intolerance to imatinib.

Intensive Imatinib in Combination With High Dose Chemotherapy Yields Improved Early Event-Free Survival in Children With Philadelphia Chromosome- Positive ALL

Kirk R. Schultz, MD, Children's Oncology Group, Arcadia, California, reported on results of Children’s Oncology Group (COG) Study AALL0031, which demonstrated an association between intensive imatinib (Gleevec) therapy in conjunction with high-dose chemotherapy and improved early event-free survival in children with Philadelphia chromosome positive (Ph ) acute lymphoblastic leukemia (ALL).

The COG AALL0031 protocol (open 2002 —2006) gave imatinib at 340 mg/m2 for an increasing number of days in combination with an intensive chemotherapy backbone. Cohorts received 42 days of imatinib exposure (Cohort 1, N=8), 63 days (Cohort 2, N=12), 84 days (Cohort 3, N=11), 126 days (Cohort 4, N=12) and 280 continuous days (Cohort 5, N=50) prior to maintenance therapy. If an HLA-identical sibling donor was available, a bone marrow transplant (BMT) was performed after the first two cycles of therapy postinduction otherwise chemotherapy was continued. The BMT patients received imatinib starting 4—6 months post-BMT for a 6-month duration. Ninety-three patients were treated, 10 of whom had failed induction (induction failures were removed from the following analyses).

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Researchers observed that minimal residual disease (MRD) positivity (<0.01%) was significantly lower (= 0.0002) after consolidation block 1 and after consolidation block 2 (= 0.007) in Cohorts 3—5 (imatinib in consolidation blocks 1&2) versus Cohorts 1 and 2 combined (no imatinib in consolidation blocks 1&2). Early event-free survival (EFS) improved with increasing imatinib exposure with a one-year EFS of 70.6±11.1% for Cohorts 1 & 2, 90.9±6.4% for Cohorts 3&4, and 95.3±3.6% for Cohort 5 (P = 0.02). The one year EFS for Cohort 5 was significantly higher than for historical controls from previous COG studies (N=56; one-year EFS 65.7±6,4%; = 0.006). Twenty-one patients had matched sibling transplants (8 of 43 in Cohorts 1—4 and 13 of 44 in Cohort 5). Eleven of 83 (13%) patients were removed from protocol by treating institutions for alternative donor BMT. Intent-to-treat analysis does not show a statistically signifi- cant difference in early outcome between those patients in Cohort 5 treated without sibling donor BMT compared with patients who received a matched sibling donor BMT ( = 0.26).

The related donor BMT group treated with 6 months of imatinib post BMT had a higher one-year EFS compared with a comparable historical BMT group receiving no imatinib on prior pediatric cooperative group protocol with a one-year EFS 78%. Cohort 5 chemotherapy treatment group outcomes were not significantly affected after removal of patients receiving off protocol BMT.

Schultz and colleagues concluded that imatinib given in combination with intensive chemotherapy resulted in a significant improvement in early EFS and reduction in early MRD. Post-BMT imatinib also improved early outcome in related donor BMT. Intensive imatinib with intensive chemotherapy gives equivalent early EFS to patients treated with allogeneic-related or alternative- donor BMT. According to researchers, longer observation will be required to see if this results in a difference in long term EFS.

Currently, Ph ALL remains one of the highest risk subsets of childhood ALL.

Outcome in patients on Children's Oncology Group protocol, AALL0031

Therapy given

N

One-year EFS

SE

Intent-to-treat analysis - Cohort 5 chemotherapy with continuous-dosing imatinib

(includes 6 patients removed from study for alternative donor BMT) specifi city

31

96.7%

3.5%

Intent-to-treat analysis - Sibling BMT (all Cohorts)

21

95.0%

5.3%

Cohort 5 (with removal of alternative-donor BMT patients)

25

95.8%

4.3%

Off protocol alternative donor BMT (all cohorts)

11

81.8%

12.3%

BMT= Bone marrow transplant; N= number; EFS= event-free survival; SE= standard error.

Dasatinib Shows Promise as Front-Line Monotherapy for Induction Treatment in Adult and Elderly Philadelphia Chromosome—Positive ALL

Robert Foa, MD, Department of Cellular Biotechnologies and Hematology, University of Rome, presented the first interim results of the GIMEMA protocol LAL 1205, a study designed to assess the efficacy, safety and tolerability of dasatinib (Sprycel) in Philadelphia chromosome—positive acute lymphoblastic leukemia (Ph ALL) patients at the onset of the disease.

The protocol enrolls patients 18 years or older who receive oral dasatinib at a dose of 70 mg. A steroid regimen (twice daily prednisone up to 60 mg/m2 day) is started seven days prior to the first dasatinib administration and is continued until day 31. The seven-day prednisone pre-phase allows identification of the BCR/ABL transcript. Dasatinib is administered for a total of 84 days. Two intrathecal methotrexate infusions at days 22 and 43 are included. All cases are processed and analyzed through central handling of samples at presentation and are investigated for morphology, immunophenotype, cytogenetics and molecular biology. Minimal residual disease (MRD) is also centrally evaluated by flow cytometry and Q-RT-PCR at days 22, 43, 57 and 84.

Days

Immunophenotype (% of leukemic cells)

Q-RT-PCR (copy number)

<3% - >1%

<1% - >0.01%

<0.01%

0%

>1 x 10²

<1 x 10²

22

3/18 pts

8/18 pts

7/18 pts

0/18 pts

11/20 pts

9/20 pts

43

0/17 pts

4/17 pts

12/17 pts

1/17 pts

5/20 pts

15/20 pts

57

0/16 pts

4/16 pts

12/16 pts

0/16 pts

2/19 pts

17/19 pts

84

0/16 pts

4/16 pts

11/16 pts

1/16 pts

4/16 pts

12/16 pts

A total of 23 patients with BCR/ABL ALL have been enrolled to date; median age 57 yrs (30—74), 15 females. All 23 patients have shown a complete hematological response by day 22. One patient relapsed after completing dasatinib administration and died of disease progression, while all other patients are at present alive and well after a median time of observation from diagnosis of 4.5 months (1.7–8.0). Monitoring of MRD documented that dasatinib plus prednisone was capable of inducing a very marked clearance of leukemic cells already at day 22, confirmed and strengthened in the subsequent steps of observation. The results of the immunophenotypic and BCR/ABL Q-RT-PCR monitoring are reported in the above Figure.

This interim analysis indicates that in adult and elderly Ph ALL induction, monotherapy with dasatinib plus prednisone is capable of inducing a rapid hematological remission in all patients so far treated without important toxicity and no fatality. This is associated with a very marked and rapid debulking of the disease as documented by the close phenotypic and molecular monitoring of MRD.

Six-Year Follow-Up Links Imatinib to Sustained Survival and Declining Annual Rates of Transformation in Patients with Newly Diagnosed CML in Chronic Phase

Andreas Hochhaus, MD, University of Heidelberg, Mannheim, Germany, reported on the results of a six-year follow up to the International Randomized study of Interferon versus STI571 (IRIS), which demonstrated that imatinib (Gleevec) has superior safety and efficacy relative to interferon-a plus cytarabine (IFN ARA-C) in the treatment of newly diagnosed chronic myeloid leukemia (CML).

In the study, 1,106 patients were randomly assigned to either imatinib or IFN ARA-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations.

Data from the six-year follow-up have shown that the downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of the 553 patients who were randomized to imatinib, 364 (65.8%) remain on the study drug at six years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) discontinued imatinib therapy.

The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with two additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, six patients lost CCyR but remain in MCyR, and the remaining nine patients never had a documented CCyR.

Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at six years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after electing to opt for stem-cell transplantation (SCT), 27 not because of CML).

Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at six years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis.

Findings from the 6-year follow-up analysis of the IRIS population indicate that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.

Efficacy of Nilotinib Affirmed in Patients with Newly Diagnosed, Previously Untreated Philadelphia Chromosome-Positive CML in Early Chronic Phase

Jorge Cortes, MD Anderson Cancer Center, Houston, Texas, reported the results of a study that evaluated the efficacy of nilotinib (Tasigna) as first-line therapy in patients with newly diagnosed Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) in early chronic phase (CP). The primary objective of the clinical trial was to estimate the proportion of patients attaining major molecular response (BCR-ABL/ABL ratio ≤0.05%) at 12 months.

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Thirty-two patients were treated with nilotinib 400 mg orally twice daily for a median of five months (range: 1 to 31 mo). The median age of study participants was 47 years (range: 24—73 yr). The rate of complete cytogenetic response (CCyR) (Ph 0%) at 3, 6 and 12 months compared favorably with those observed in historical controls treated with imatinib 400 mg or 800 mg daily. At three months, 21 of 22 patients (95%, < 0.0001) attained CCyR. At six months, all 13 evaluable patients achieved CCyR (100%, < 0.0001). At 12 months, all 11 evaluable patients demonstrated CCyR (100%, < 0.0007). In contrast, historical CCyR for low-dose (400 mg) imatinib were 37%, 54%, and 65% at 3, 6, and 12 months. respectively. Historical CCyR for high-dose (800 mg) imatinib were 62% at three months, 82% at six months, and 86% after one year.

At three month follow-up, major molecular response (MMR) was observed in 3 of 22 patients (14%). At six months, MMR was attained by 7 of 13 patients (54%). At 12 months, 5 of 11 (45%) patients demonstrated MMR. None of the molecular responses has been lost while on therapy.

Commenting on the data, lead study author Dr. Cortes stated, “these are early results, but certainly encouraging.”

Study findings suggest that nilotinib dosed at 400 mg orally twice daily offers significant efficacy manifested by complete cytogenetic responses in nearly all patients, as early as three months after the initiation of therapy. Additionally, the agent was shown to have a favorable toxicity profile.

Dasatinib Shown to be Efficacious Option for Patients With Chronic-Phase CML With Resistance or Intolerance to Imatinib

Richard M. Stone, MD, Dana-Farber Cancer Institute, Boston, reported the results of two-year follow-up data from the START-C trial, a study evaluating dasatinib (Sprycel) efficacy in patients with chronic- phase chronic myelogenous leukemia (CP-CML) with resistance or intolerance to imatinib (Gleevec). In the Phase II Trial, dasatinib was administered on a 70-mg bid regimen to 387 patients with CP-CML with resistance or intolerance to imatinib. Of the 387 study participants, 288 were imatinib resistant and 99 were imatinib intolerant.

Complete hematologic response (CHR) was attained in 91% of patients (95% CI 87%—93%), major cytogenetic response (MCyR) in 59% (95% CI 54%–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and complete cytogenetic response (CCyR) in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib.

A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only seven of the 230 patients who had achieved a MCyR with dasatinib losing this response. Progression- free survival at 15 months was 90% while overall survival was 96%.

The follow-up data from the START-C study demonstrated continuing dasatinib efficacy across patient subgroups, including all but one of 43 different mutations identified at baseline, and patients with P-loop mutations or no prior CyR to imatinib. Dasatinib-induced cytogenetic responses remain durable in patients who were CP-CML resistant or intolerant to imatinib. In addition, dasatinib was shown to be well tolerated, evidencing a lack of cross-intolerance to imatinib. “Dasatinib is a major advance for people who can't take imatinib because of intolerance or who shouldn't take it because of resistance,” concluded Dr. Stone.

%u25BA Advances in Lymphoma

ASH attendees demonstrated a keen interest in breaking research that centered around novel treatments and approaches for the more than 30 subtypes of disease that comprise lymphoma (consisting of five types of Hodgkin’s lymphoma [HL] and over 25 types of non-Hodgkin’s lymphoma [NHL]). Hodgkin’s lymphoma is a less common form of the disease. Of the nearly 500,000 Americans with lymphoma, over 142,000 have Hodgkin’s lymphoma.

Lymphoma, often called the “Rosetta Stone” of cancer research because it has helped unlock the mysteries of several other types of cancer, continues to offer several promising avenues of research. Researcher focus has included:

• Determining the exact role of viruses in causing HL;

• New antibody treatments, which act like guided missiles that zero in on specific targets (antigens) on the lymphoma

cells;

• The development of less toxic and lesser amounts of chemotherapy and radiotherapy (even though the cure rate of

HL is high, the current treatments themselves may have long-term toxic effects).

Owing to the rapid pace of lymphoma-related clinical advances over the past few years, it is estimated that over 80% of patients with HL, for example, can now be cured. Recent advances in research and treatment are occurring at a fortuitous time: Since the 1970s, incidence rates for NHL have nearly doubled. Since the risk of developing NHL increases throughout life, the aging of the American population is likely to lead to a further increase in non-Hodgkin lymphoma cases during the coming years. Furthermore, outcomes for NHL lag behind those of HL patients. Currently, the overall five-year NHL survival rate is only 59%.

Data presented at the meeting showed improved overall survival or prolonged progression-free survival in HL and follicular NHL. At a press conference highlighting the lymphoma data, Jane Winter, MD, Division of Hematology Oncology, Northwestern University, Chicago, Illinois, stated, “The research presented at this year’s meeting will have important clinical benefits for patients.”

Pretransplant Rituximab Therapy Associated with Improved Survival in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma

Timothy S. Fenske, MD, Center for International Blood & Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, presented the results of a study that examined the outcomes of 1,006 patients who underwent peripheral blood autologous hematopoietic stem cell transplantation (AuHCT) for diffuse large B-Cell lymphoma (DLBCL) between 1996 and 2003, 188 of whom underwent pretransplant therapy with chimeric anti-CD20 monoclonal antibody rituximab (Rituxan) and 818 of whom did not. Findings indicated that patients enrolled in the rituximab arm of the study demonstrated improvement in both progression- free and overall survival.

There were no significant differences between the two arms of the study with regard to gender, pretransplant performance status, disease status at transplant, pretransplant chemosensitivity, second-line aa-IPI score distribution, Ann Arbor stage at transplant, interval from diagnosis to transplant, bulky disease, bone marrow involvement, posttransplant radiation therapy, or posttransplant myeloid growth factor therapy.

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Progression-free survival (PFS) at 1 and 3 years was superior in the group that underwent pre-transplant rituximab therapy (62% vs. 49% at 1 year, = 0.002; 49% vs. 38% at 3 years, = 0.010). Overall survival (OS) was superior in the rituximab group (68% vs. 60% at 1 year, P = 0.032; 57% vs. 45% at 3 years, = 0.003). Treatment-related mortality at 1, 3, or 5 years did not differ significantly between the group that underwent rituximab therapy before transplant and the group that did not.

The study showed that in patients undergoing AuHCT for DLBCL, pretransplant rituximab is associated with improved PFS and OS following AuHCT. Moreover, according to study authors, no evidence associated rituximab with impaired engraftment or increased treatment-related mortality.

Safety of 90Yttrium Ibritumomab Tiuxetan Combined with BEAM Conditioning Regimen Plus Autologous Stem Cell Transplantation Affirmed in Relapsed or Refractory Follicular Lymphoma

Christian Gisselbrecht, MD, Hemato-oncology, Saint Louis Hospital, Paris, France, presented results of a phase II study designed to evaluate the efficacy and toxicity of 90Yttrium ibritumomab tiuxetan (Zevalin) combined with BEAM conditioning regimen (carmustine, etoposide, cytosine- arabinoside, and melphalan) prior to autologous stem cell transplantation (ASCT) in relapsed or refractory follicular lymphoma.

Subjects received a 15 MBq/kg (maximum 1200 MBq, total dose) dose of 90Yttrium ibritumomab tiuxetan without dosimetry day -14 before ASCT and combined to standard BEAM regimen starting at day-7.

Patients under 65 years of age with CD20 low grade B cell lymphoma in 1st or 2nd relapses, or not achieving complete remission after first-line treatment were included in the trial. Subjects had to be chemosensitive to last salvage therapy, no more than three lines of treatment and eligible for ASCT. The primary end point was to detect a two-year event-free survival (EFS) of at least 80%. Hematological reconstitution was evaluated after transplant and during the first year follow up.

The hematological reconstitution after 90Yttrium ibritumomab tiuxetan combined with carmustine, etoposide, cytosine-arabinoside, and melphalan (Z-BEAM) followed by ASCT in 75 patients was: time to neutrophils less than 1G/L 12 days (9—35), time to platelets less than 20 G/L 12 days (3–42). Median number of platelets transfusions 4; red blood cell transfusions 2. Grade 3–4 toxicities were: infection 83%, mucositis 47%, pulmonary 4%. Safety data indicated 35 serious adverse events in 24 patients that did not appear to significantly differ from those usually seen after ASCT. No toxic death was observed. At week 12 and 42 after ASCT, median hemoglobin levels were 11.6 g/dL and 11.3 g/dL, median platelets counts was 111G/L and 148 G/L, leucocytes counts 3.48 G/L and 4.80 G/L respectively. Only five events were reported. After a minimum follow up of one year for all patients, estimated two years EFS is 93%.

The study demonstrated that Z-BEAM is a safeconditioning regimen that can be used to treat B-cell lymphoma. According to Gisselbrecht and colleagues, longer follow up is necessary to evaluate long-term toxicity and efficacy.

Patterns of Care in Follicular Lymphoma: Are Minorities Treated Differently? Chadi Nabhan, MD, Oncology Specialists SC, Park Ridge, Illinois, reported on the evaluation of results from the National LymphoCare Study (NLCS), a prospective, longitudinal, multicenter, observational study that enrolls patients with newly diagnosed follicular lymphoma (FL) and collects data on their disease presentation, treatment patterns, and outcomes.

Using NLCS, researchers evaluated demographics, disease presentations, and patterns of care in flamong African-American (AA), Hispanic (H), and white (W) patients. The data suggest that certain baseline characteristics (i.e., age, Follicular Lymphoma International Prognostic Index (FLIPI) at diagnosis) and treatment approaches (specifically, the utilization of anthracyclines among those receiving chemotherapy) tended to vary by race.

As of January 31, 2007, 87 AA, 118 H, and 2314 W patients were enrolled in the NLCS. African Americans accounted for 3.4% and H for 4.6% of total registered patients. Despite the small numbers, this represents the largest U.S.-based database available for AA and H patients with FL. Data collection included information on grade, stage, B symptoms, FLIPI, and treatment choice.

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Two statistically significant differences in baseline characteristics were that AA patients were younger and had a poorer FLIPI at diagnosis compared with W patients. Looking at initial treatment patterns, the only difference was the use of anthracyclines among those receiving chemotherapy, with W patients more likely to receive an anthracycline-based regimen than AA patients (65.8% vs. 46.8%, = 0.01). The higher use of anthracyclines in W compared with AA patients persisted regardless of FLIPI score. Aside from anthracycline use, there were no major differences in treatment approaches and choices according to grade of disease between AA, H, or W patients. AA patients with grades 1 or 2 flreceived less anthracyclines compared with W pts (37.5% vs. 56.4%, = 0.04). The small number of AA patients with grade 3 disease precluded a meaningful comparison with W patients in this subgroup.

In conclusion, while the numbers are small, the NLCS provides the largest prospective registry information on AA and H patients. According to the NLCS data presented, AA patients, who were younger and had a poorer FLIPI at diagnosis, also received less anthracycline-based therapies than W patients, whereas H and W patients were treated similarly. Further analyses are required to understand the underlying reasons for these observed differences. Long-term follow-up will determine if outcomes vary in these patient cohorts.

Bortezomib Yields Durable Responses in Patients with Relapsed or Refractory Mantle Cell Lymphoma Andre Goy, MD, Hackensack University Medical Center, Hackensack, New Jersey presented updated time-to-event analysis data in all patients, by response category, with extended follow-up, drawn from the multi-center PINNACLE study. Previously reported PINNACLE study results (JCO 2006;24:4867—74), which resulted in approval of bortezomib (Velcade) for mantle cell lymphoma (MCL) following 1 or more prior therapies, demonstrated substantial activity with single-agent bortezomib in patients with relapsed or refractory MCL. All patients, announced Dr. Goy, have now completed treatment.

Dr. Goy and colleagues reported that after a median follow-up of 26.4 months, 55 patients (35%) remained in follow-up; 93 (60%) had died, 2 (1%) had withdrawn consent, and 5 (3%) were lost to follow-up. Patents received a median of 4 treatment cycles (range 1—21; 8 in responding patients). Median time to first response was 1.3 months. Median duration of response (DOR) was 9.2 months in all responders and has not been reached in patients achieving complete response/ unconfirmed complete response (CR/Cru). Median time to progression (TTP), time to next therapy (TTNT; first bortezomib dose to start of next therapy), and overall survival (OS) are shown in the Table for all patients and by response.

In the PINNACLE study, 155 patients (median age 65 yrs; 55%/41%/4% with 1/2/3 or more prior therapies; 77% Stage IV MCL; 55% positive bone marrow) received bortezomib 1.3 mg/ m2 on days 1, 4, 8, and 11 of 21-day cycles; of these, 141 were response-evaluable. Response and progression were determined by modified International Workshop Response Criteria using independent radiology review.

Survival rate at 12-months was 69% overall and 91% in responding patients. In patients refractory to their last therapy (no response or response with TTP less than 6 months; n=58), median DOR was 5.9 months, median TTP was 3.9 months, median TTNT was 4.6 months, and median survival was 17.3 months. Safety profile was similar to previously reported; most common grade (greater than or equal to grade 3) adverse events (AEs) were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). The most common AE resulting in bortezomib discontinuation was peripheral neuropathy (10%). Twelve (8%) patients died on-study, including 5 (3%) considered related to bortezomib.

According to Goy and colleagues, these findings demonstrate that bortezomib provides durable responses plus prolonged time off - therapy and survival in responding patients, suggesting substantial clinical benefit in relapsed/ refractory MCL.

%u25BA Advances in MDS

It is estimated that between 10,000 and 15,000 new cases of myelodysplastic syndromes (MDS), a group of conditions caused by abnormal blood-forming cells of the bone marrow, occur each year. Incidence of MDS is on the rise. Experts attribute the rise in MDS prevalence to the aging population (most patients with MDS are older than 60 years of age) and the increase in cancer survivors who have had chemotherapy (the most important MDS risk factor).

Increasing prevalence rates are exacerbated by the severity of MDS sequelae: Complications of MDS include life-threatening infections and bleeds, as well as bone marrow failure. In about three out of 10 cases, MDS transforms into acute myeloid leukemia. MDS patients have a median survival of four months to five years depending on risk stratification. Higher-risk patients have a median survival of five to 14 months.

For researchers, however, MDS presents a unique set of challenges. Efforts at MDS diagnosis and treatment are assailed by uncertainty and mystery. “It seems nobody (truly) understands MDS,” explained Mitchell Weiss, MD, PhD, Children's Hospital of Philadelphia, and Science Co-Chair of ASH, “(it is a condition) that needs a major research breakthrough.”

The horizon, however, is not without encouraging signs. While ASH 2007 may not have yielded revolutionary MDS advances, significant progress was evidenced by presented research.

Azacitidine Treatment Found to Prolong Overall Survival in Higher-Risk MDS Patients Compared With Conventional Care Regimens

Pierre Fenaux, MD, Clinical Hematology, Hospital Avicenne, Bobigny, France and The International Vidaza High-Risk MDS Survival Study Group announced complete results from the AZA-001 Phase III multicenter, international, randomized study of azacitidine (Vidaza) in the treatment of patients with higher-risk myelodysplastic syndromes (MDS) demonstrating that azacitidine provides a significant survival benefit compared with conventional care regimens (CCR) in higher- risk MDS patients.

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With a median follow-up of 21.1 months, azacitidine demonstrated a statistically significant overall survival advantage over CCR (24.4 mo vs. 15 mo; stratified log rank = 0.0001). At two years, azacitidine demonstrated a two-fold advantage in overall survival over CCR (51% vs. 26%; log rank < 0.0001). The differences translated into a hazard ratio of 0.58, representing a 42% reduction in mortality risk (= 0.0001). Among patients with poor cytogenetic profiles (as defined by the International Prognostic Scoring System (IPSS), 28% of enrolled patients), median survival was 17.2 months in the azacitidine arm, compared with six months in the CCR arm (log rank = 0.01).

“Extensive subgroup analysis demonstrated a consistent advantage in favor of azacitidine,” said Dr. Fenaux, the study’s principal investigator. Additionally, 45% of patients treated with azacitidine achieved transfusion independence compared with 11% of patients in the control arm. All secondary endpoints favored azacitidine, including the rate of transformation to AML.

"The data from this trial further confirm that Vidaza should be considered first-line therapy for patients with higher-risk MDS. The results from this trial are robust and clinically meaningful and represent an important advance in the treatment of higher-risk MDS patients," stated Dr. Fenaux.

The primary objective of the trial, which, according to azacitadine’s manufacturer, represents the largest clinical trial in MDS to date, was to demonstrate superiority in overall survival of azacitadine versus CCR in higher-risk MDS patients. The study evaluated 358 higher-risk MDS patients at sites in the United States, Europe, and Australia. At baseline, approximately 90% of patients were considered to have higher-risk MDS, based on subsequent independent review of FAB subtypes or IPSS classification. Patients were assigned to treatment with azacitadine (N=179; 75 mg/m2/day SC for seven consecutive days every 28 days) or CCR for the treatment of MDS. Patients assigned to CCR could receive either best supportive care (BSC) alone (N=105), low-dose cytarabine (LDAC; N=49), or standard chemotherapy (StdChemo; N=25).

Dr. Fenaux and colleagues concluded the azacitadine treatment, compared with CCR, yields an enhanced survival benef t that is statistically significant and consistent across patient subgroups. “For all endpoints studied, for all subgroups studied, azacitidine showed superiority over [conventional care]," stated Dr. Fenaux. Moreover, azacitadine was found to be well tolerated, demonstrating a safety profile consistent with previous experience.

Lenalidomide Associated with Significant Therapeutic Response in Intermediate 2 and High-Risk Myelodysplastic Syndrome with 5q Deletion

Sara Burcheri, MD, Groupe Francophone des Myelodysplasies (GFM), Hospital Avicenne, Bobigny, France, presented interim results from a phase I-II study of lenalidomide (Revlimid)(10 mg/ day x21days q 28 day, increased to 15mg/day after 2 cycles, in the absence of response and dose limiting toxicity (DLT) in myelodysplastic syndromes (MDS) with 5q deletion (del 5q) and high-risk or intermediate-2 MDS, as defined by the International Prognostic Scoring System (IPSS).

Between November 2006 and July 2007, 49 patients from nine centers were included. Thirty of these patients, included more than eight weeks before first interim analysis (July 1, 2007), are analyzed here: 15 females, 15 males, median age 68 (range 35—85). Four patients had received previous chemotherapy (2 LD AraC, 2 anthr-AraC). Two patients had refractory anemia (RA), six had refractory anemia with excess blasts-1 (RAEB-1), 12 had refractory anemia with excess blasts-2 (RAEB-2), and 10 had refractory anemia with excess blasts in transformation (RAEB-T). Nineteen patients were IPSS high and 11 were IPSS intermediate 2. Del 5q was isolated, with one additional and more than one additional abnormality in four, eight and 18 patients respectively (in the last group, median number of additional abnormality was 5, range 2–22). All patients had transfusion dependent anemia.

Platelets (Plts) were < 100G/L in 16 patients (5 required plt transfusions) and absolute neutrophil count (ANC) <1.5G/L in 28 patients. Median number of days of lenalidomide received was 34 (range 14—126). Dose reduction to 5 mg/day or 5mg/2day was required in 11 patients and one patient respectively, because of thrombocytopenia (N=9) neutropenia (N=2), and rash (N=1). 1 patient stopped lenalidomide after two weeks, for unrelated disorder without evidence of progression, and was excluded from analysis. six of the 29 evaluable patients (21%), had response (2 complete response CR, 2 partial response PR, 2 erythroid response HI-E). three (10%) patients died during the fi rst course, from sepsis (2), cardiac failure (1) and the remaining 20 patients progressed within the two fi rst cycles. All responses were observed after 2 cycles. Two and three of the responders achieved complete and partial cytogenetic response, respectively. Duration of CR, PR, and HI-E was 5 and 4 months, 5 and 4 months, 2 and 2 months, respectively. CR or PR was achieved in 4/12 patients (33%) with isolated del 5q or with single additional abnormality versus 0/17 pts with >1 additional abnormality; 3/19 pts (16%) with <20% blasts versus 1/10 with >20% blasts; and 4/14 (29%) with initial plts > 100G/L, versus 0/15 patients with lower plts. Eighteen patients were alive and 11 patients had died after 6 to 210 days (median 80) from early death (N= 3, as seen above) or progression (N=8). Nonfatal serious adverse events were sepsis (10), cardiac failure (2), CNS bleeding (1), thrombosis (1), ischemic colitis, (1) pulmonary embolism). Hospitalization was required in 28/29 patients during treatment. Median number of RBC and Plt transfusions during each cycle was 4 and 1.5 respectively. Four patients (all responding) remained on study.

Researchers concluded the lenalidomide, as a single agent therapy, at the dose used, yielded significant responses in high and intermediate 2 MDS with del 5q in the absence of cytogenetic complexity and of thrombocytopenia, while other patients generally progressed rapidly. Significant myelosuppression, requiring hospitalization in almost all cases, was observed. Burcheri and colleagues suggested that higher lenalidomide doses, and/or combination to cytoreductive or hypomethylating agents, may improve results.