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Keywords:

  • chronic myelomonocytic leukemia;
  • myelodysplastic syndrome;
  • 9-nitro-camptothecin

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Topoisomerase I inhibitors, like topotecan, have activity in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). 9-Nitro-camptothecin (9-NC) is a new oral topoisomerase inhibitor with a good safety profile. The aims of the current study were to evaluate the activity and safety of 9-NC in MDS and CMML.

METHODS.

Adults with a diagnosis of MDS (n = 12) and CMML (n = 32) received 9-NC 2 mg/m2 orally daily 5 days a week, every 4 to 6 weeks.

RESULTS.

Overall, 5 (11%) patients achieved complete response (CR), 7 (16%) had a partial response (PR), and 6 (14%) had hematologic improvement (HI), for an overall response rate of 41%. The response rate was similar in MDS and CMML. Severe (Grade 3–4) side effects included nausea and vomiting (7%), diarrhea (18%), other gastrointestinal toxicities (5%), and genitourinary toxicities (12%).

CONCLUSIONS.

9-NC is active in MDS and CMML. The paucity of available therapies in CMML makes 9-NC a good candidate for further studies as a single agent, or in combination with decitabine, 5-azacitidine or cytarabine. Cancer 2006. © 2006 American Cancer Society.

Myelodysplastic syndrome (MDS) is a group of disorders characterized by dysplastic changes in the myeloid, erythroid, and megakaryocytic series.1 These result in cytopenias in 1 or more lineages. Patients present with complications related to anemia (fatigue), neutropenia (infections), or thrombocytopenia (bleeding). Depending on the French-American-British (FAB) MDS subset and karyotype, in 10% to 70% of patients MDS may evolve into an acute leukemia. A new International Prognostic Scoring System divides patients into low, intermediate 1, intermediate 2, and high risk categories with median survivals of 5.7, 3.1, 1.2, and 0.4 years, respectively.2

Therapies in MDS have included supportive care, growth factors (erythropoietin, G-CSF, GM-CSF), immune therapy, intensive chemotherapy, allogeneic stem cell transplantation (SCT), and low intensity or differentiating agents (low-dose cytarabine, azacitidine). Azacitidine was the first agent approved by the Food and Drug Administration for the treatment of MDS, and another hypomethylating agent, decitabine, has also recently been approved.3, 4 Intensive chemotherapy induces complete responses (CR) in 40% to 50% of patients, but is associated with serious morbidity. Remissions after intensive chemotherapy are short-lasting.5 Lenalidomide, an immunomodulating inhibitory derivative of thalidomide, has shown major activity in lower-risk MDS with deletion of chromosome 5q31.1.6 Among 148 patients treated with lenalidomide, the red cell transfusion independence rate was 66% and the complete cytogenetic response rate 44%.7 Other investigational agents include clofarabine, homoharringtonine, and others.8, 9

Chronic myelomonocytic leukemia (CMML) is a hybrid myeloproliferative-dysplastic disorder manifesting with proliferation of the myeloid series and dysplasia of the erythroid-megakaryocytic series.10, 11 Originally considered part of MDS, it is now categorized as a separate entity.12 Patients with CMML are generally older (median age, 60–65 years) and exhibit male predominance. Common presentations include fatigue and anemia, neutropenia, thrombocytopenia and bleeding, and splenomegaly. Prognosis in CMML is poor, with a median survival of 18 to 20 months. Therapy of CMML includes supportive care, growth factors, hydroxyurea, intensive acute myeloid leukemia (AML)-type therapies, topotecan and cytarabine, splenectomy (for significant refractory splenomegaly and hypersplenism/cytopenias), and allogeneic SCT. The only approved therapies for CMML are 5-azacitidine and decitabine. The studies resulting in the FDA approval of these drugs included fewer than 10 patients each with CMML,3 the approval being part of the blanket approval for MDS, rather than an expanded specific study in CMML.

Topoisomerase I inhibitors like topotecan have shown significant activity in MDS and CMML. Single-agent topotecan was associated with a CR rate of 30%.13, 14 Combinations of topotecan plus cytarabine resulted in CR rates of 50% to 60% in MDS and CMML.5, 15

A new oral topoisomerase I inhibitor, 9-nitro-20-(s) camptothecin (9-NC) (Supergen, Dublin, CA), had shown preliminary encouraging activity in patients with MDS and CMML (Fig. 1). 9-NC was chosen for expanded studies in MDS and CMML for several reasons: 1) the relatively indolent courses of MDS and CMML; 2) the oral formulation of 9-NC, making its administration easier for patients with MDS and CMML; 3) the need for lower-dose longer-exposure schedules; and 4) the previously documented activity of topotecan in MDS and CMML.

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Figure 1. Structure of 9-nitro-camptothecin.

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MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Group

Adults with a diagnosis of higher-risk MDS by FAB (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEBT]) or CMML were entered into the study after informed consent was obtained according to institutional guidelines. Eligibility criteria required an age ≥16 years old, adequate performance status of 0 to 2 (ECOG scale), and adequate liver (bilirubin ≤1.5 mg/dL) and renal functions (creatinine ≤1.5 mg/dL). Patients were required not to have received more than 1 prior regimen or biological therapy, prior high doses of cytarabine (≥1 g/m2 daily), or chemotherapy for at least 2 weeks before receiving 9-NC, and to have recovered from the side effects of prior therapy. Nursing females were excluded and patients of child-bearing potential were required to practice effective birth control measures.

Therapy

9-NC was given orally daily at a starting dose of 2 mg/m2 daily for 5 days, every week. Courses were repeated every 4 to 6 weeks depending on side effects and recovery of counts. If no side effects were noted, patients received 9-NC orally daily × 5 every week continuously. In the presence of Grade 3–4 extramedullary side effects, the treatment was interrupted until resolution of toxicity to Grade ≤1, then resumed at a lower dose level (25% dose reduction, rounded to 1.5 mg/m2, daily × 5 for −1 level; 1.5 mg/m2 daily × 4 for −2 level). 9-NC was given in 2 equal divided doses, i.e., 1 mg/m2 orally twice daily. If patients experienced drug-related lower counts (granulocytes <109/L, platelets <50 × 109/L), 9-NC was interrupted and resumed when granulocytes recovered to >109/L and platelets to >80 × 109/L.

Response Criteria

This study was designed in 1995, before the proposed response definitions in MDS by the International Working Group (IWG) criteria. Response definitions were based on then-accepted response criteria. A complete response (CR) required normalization of the peripheral blood and bone marrow with ≤5% blasts, granulocytes ≥109/L, and platelets ≥100 × 109/L, the response lasting for at least 4 weeks. A partial response (PR) required improvement of at least 2 of the following parameters: 1) platelets increase by 100% and to above 50 × 109/L (if pretreatment values were below this level); 2) granulocytes increase by 100% and to above 109/L (if pretreatment values were below this level); 3) hemoglobin increase by 2 g/dL or more if it was below 10 g/dL; or 4) reduction of marrow blasts to ≤5% if the pretreatment value was >10%. These responses should last for at least 4 weeks. Transient cytopenias due to drug-related myelosuppression, infections, or other factors known to cause myelosuppression did not interrupt evaluation of response duration. Patient responses were also evaluated by the new proposed IWG criteria.16, 17 Toxicity was graded according to the NCI Common Toxicity Criteria v. 2.0.

Survival was dated from the start of therapy. Remission duration and survival curves were according to the Kaplan-Meier method.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 44 patients were treated, including 12 patients with MDS and 32 patients with CMML. Their median age was 68 years (range, 29–81 years); 17 (39%) patients were females. The characteristics of the study group are detailed in Table 1.

Table 1. Characteristics of the Study Group (n = 44)
ParameterCategoryNo. (%)
MDS (n = 12)CMML (n = 32)Total (n = 44)
  • MDS indicates myelodysplastic syndrome; CMML, chronic myelomonocytic leukemia; WBC, white blood cell; FAB, French-American-British; WHO, World Health Organization.

  • *

    Three with prior splenectomy.

  • Among patients with CMML, only those with nonproliferative disease (n = 4 in this series) were evaluable by the International Prognostic Scoring System (IPSS).2

Age, y≥6012 (100)23 (72)35 (80)
[median]746668
GenderFemale5 (42)12 (38)17 (39)
Splenomegaly (n = 41)*Yes1 (8)12 (38)13 (27)
Hemoglobin (g/dL)<107 (58)11 (34)18 (41)
Platelets (× 109/L)<506 (50)14 (44)20 (46)
>1003 (25)14 (44)17 (39)
WBC (× 109/L)>5007 (22)7 (16)
Percent monocytes≥104 (33)17 (53)21 (48)
Percent bone marrow blasts6–101 (8)5 (16)6 (14)
>108 (67)4 (13)12 (27)
FAB subgroupRAEB8 (67)8 (18)
RAEBt4 (33)4 (9)
CMML32 (100)32 (73)
WHO subgroupRAEB-13 (25)3 (7)
RAEB-26 (50)6 (14)
CMML-126 (81)26 (59)
CMML-25 (16)5 (11)
AML3 (25)1 (3)4 (9)
IPSSLow1 (8)2 (50)3 (19)
Int-101 (25)1 (6)
Int-24 (33)1 (25)4 (25)
High2 (17)02 (13)
Chromosomal abnormalitiesNone5 (42)21 (66)26 (59)
Chromosome 5 or 75 (42)1 (3)6 (14)
Others2 (17)10 (31)12 (27)
Duration of disease, mo<66 (50)20 (63)26 (59)
6 – 1203 (9)3 (7)
>126 (50)9 (28)15 (34)
[median]1244
Prior therapyNone7 (58)19 (59)26 (59)
Biological2 (17)6 (19)8 (18)
Chemotherapy3 (25)7 (22)10 (23)
Both000
Secondary MDS or CMMLYes04 (13)4 (9)

Overall, 5 (11%) patients achieved CR, 7 (16%) had a PR, and 6 (14%) had hematologic improvement (per protocol criteria) for an overall response rate of 41%. The response rate was 41% in MDS and 40% in CMML. The 1 MDS patient with hematologic improvement according to protocol criteria (bone marrow blasts improved from 18% to 4%, hepatomegaly from 2 cm to 0 cm), did not meet criteria for this response according to IWG criteria. The response data are detailed in Tables 2 and 3.

Table 2. Response to 9-Nitro-camptothecin Therapy in MDS and CMML
ResponseNo. response (%)
MDS (n = 12)CMML (n = 32)Overall (n = 44)
  • MDS, indicates myelodysplastic syndrome; CMML, chronic myelomonocytic leukemia.

  • *

    Hematologic improvement based on protocol criteria, not by International Working Group.

Complete response3 (25)2 (6)5 (11)
Partial response1 (8)6 (19)7 (16)
Improvement1 (8)*5 (16)6 (14)
Inevaluable448
Table 3. Characteristics and Course of Responding Patients
PatientAge, yDiagnosisKaryotypePrior therapy, Yes/NoResponse/duration, monthsPercent bone marrow blasts, pre/postWBC (× 109/L), pre/postPlatelets (× 109/L), pre/postOther,* pre/post
  • CMML, indicates chronic myelomonocytic leukemia; WBC, white blood cell; RAEB, refractory anemia with excess blasts; RAEB-T, RAEB in transformation; CR, complete response; PR, partial response; HI, hematologic improvement; Hgb, hemoglobin; NE, no evaluable disease; NR, no response in parameter.

  • *

    Spleen and liver size in centimeters below costal margin; Hgb in g/dL.

  • Hematologic improvement based on protocol criteria, not by International Working Group.

166CMMLDiploidYesPR/4NE25.2/8.0NESpleen 13/6
265CMMLTrisomy 8YesHI/3.5NE76.0/8.833/NR 
365CMMLDiploidYesPR/15NE46.1/7.546/NRSpleen 11/0
477CMMLDiploidNoPR/17NE27.3/7.4NESpleen 12/1
537CMMLOtherNoCR/10NE70.5/8.8NEHgb 11.2/14.0
669CMMLDiploidYesPR/37/244.6/7.323/NR 
776CMMLDiploidNoHI/5NE43.0/8.176/120 
876CMMLOtherYesCR/1125/224.2/5.013/288 
964CMMLDiploidYesPR/18NENE43/100Hgb 10.4/14.2
1078CMMLDiploidYesHI/27/NR74.7/4.550/NR 
1169CMMLDiploidNoPR/513/49.365/178Hgb 7.5/10.5
1268CMMLOtherYesHI/3NE171.0/61.1NE 
1367CMMLDiploidNoHI/9.5NE25.0/9.139/NR 
1473RAEBChromosome 5/7 abnormalitiesYesCR/4NE18.0/5.61042/469 
1567RAEBDiploidYesHI/1518/4NE32/NRLiver 2/0
1673RAEB-TOtherNoPR/16/NR25.8/6.4NESpleen 15/4
1770RAEBDiploidNoCR/415/02.7/6.640/141 
1874RAEBChromosome 5/7 abnormalitiesNoCR/8NENE15/388 

The median number of courses (course = 4 weeks) given was 3 (range, 1–28). The median number of weeks on therapy was 16 (range, 1–161). The 2-year survival rate was 25%, 17% in MDS and 28% in CMML (Fig. 2).

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Figure 2. Survival with 9-nitro-camptothecin in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML).

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Side Effects

The most common severe side effects included diarrhea (18%), and nausea and vomiting (7%) (Table 4). Extramedullary side effects requiring dose reductions were noted in 48%. Grade 3 or higher adverse events were noted usually during cycle 1 (n = 10) or 2 (n = 3), although in 4 instances they appeared only after ≥20 cycles of therapy. All adverse events were reversible within 2 weeks of drug discontinuation, except for 3 episodes of cystitis, which required 40 to 60 days for complete resolution. These episodes were diagnosed clinically and were not associated with hemorrhage. Drug-related myelosuppression requiring dose reductions was noted in 20%. There were no deaths associated with adverse events.

Table 4. Side Effects with 9-Nitro-camptothecin (n = 44 Patients)
Side effectNo. (%)
Grade 1–2Grade 3–4
Extramedullary
Nausea, vomiting23 (52)3 (7)
Diarrhea25 (57)8 (18)
Mucositis6 (14)
Abdominal pains/gastritis/other gastrointestinal5 (11)2 (5)
Cystitis1 (2)2 (5)
Dysuria, hematuria6 (14)2 (5)
Liver function abnormalities1 (2)1 (2)
Renal function abnormalities1 (2)1 (2)
Other (fatigue, headache, rash)4 (9)
Medullary
Neutropenia15 (34)11 (25)
Thrombocytopenia21 (48)17 (39)
Fever
Unknown origin5 (11)
Documented infection14 (32)
Severe bleeding (gastrointestinal)2 (5)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this study, 9-NC demonstrated encouraging activity in MDS and CMML. The response rates achieved with 9-NC compared favorably with the results of 5-azacitidine in MDS. The side effects, mostly gastrointestinal, were acceptable, with severe diarrhea observed in 18% of patients. Thus, the profile of efficacy, oral administration, and side effects of 9-NC appears favorable and suggests the need to pursue its activity in MDS and CMML. In particular, the activity in CMML, a disease with few treatment options, makes 9-NC attractive for further development in that setting.

Topotecan, another topoisomerase inhibitor, has demonstrated significant clinical activity in patients with MDS. As a single agent, it induced complete remissions in 27% of patients with MDS and 28% of those with CMML.13 These results resulted from a continuous administration schedule of topotecan. Preclinical studies suggested that continuous exposure to a topoisomerase inhibitor might be more effective than an intermittent exposure.18 Indeed, studies using a bolus administration of topotecan resulted in a CR rate of only 6%, albeit with lower toxicity allowing for higher doses to be administered.19 This has created increased interest in the development of oral topoisomerase inhibitors that could allow for a prolonged exposure. In a Phase I study of oral topotecan for patients with MDS, CMML, or AML, responses were observed in 42% of the patients, including CR in 17%. Dose-limiting toxicities were mostly gastrointestinal.14 Another study investigated 2 different schedules of oral topotecan 1.2 mg/m2 either once a day for 10 days or twice a day for 5 days every 21 days. Adherence was similar in the 2 schedules; however, although topotecan exposure was greater in the twice-a-day arm due to drug accumulation, exposure did not correlate with clinical response.20

The comparative efficacy of 9-NC versus topotecan is difficult to assess in view of the different dose schedules and study groups. Both agents appear to show anti-MDS and -CMML activities; both are dose-limited by gastrointestinal side effects. 5-azacitidine and decitabine are currently the standard of care in MDS and CMML, and future studies may compare them to 9-NC or to the combination of 5-azacitidine or decitabine plus 9-NC. In addition, new topoisomerase inhibitors are being developed that may have an improved toxicity profile.

In summary, 9-NC, a new oral topoisomerase I inhibitor, has shown encouraging activity and safety in MDS and CMML, and should be investigated further in these conditions.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES