Table 3.
Selected published studies and reports using investigational therapies for CMML.
| Reference [#] | Drug class | Specific drug | Other drugs used |
Regimen | No. of CMML patients |
CMML-1, CMML-2 |
Age | Cytogenetics/molec info | Nonhematologic toxicities | Response |
|---|---|---|---|---|---|---|---|---|---|---|
| Beran, 1996 [142] | Topoisomerase I inhibitor | Topotecan | None | 2 mg/m2 cont IV per day × 5 days repeated every 4-8 weeks |
25 | Not reported | 21 patients (84%) ≥ 60 years |
Diploid 10 (40%), abnormal 5/7 7 (28%), 11q 2 (8%), other 2 (8%) |
Mucositis, GI, neurotoxicity most common |
28% CR |
| Beran, 1998 [143] | Topoisomerase I inhibitor | Topotecan | None | 2 mg/m2 cont IV per day × 5 days repeated every 4-8 weeks |
30 | Not reported | Including patients with MDS, 83% were > 60 years |
Not reported for CMML patients |
Mucositis, GI, neurotoxicity most common |
27% CR |
| Beran, 1999 [144] | Topoisomerase I inhibitor | Topotecan | Cytarabine | Topotecan 1.25 mg/m2 cont IV per day on days 1-5 + cytarabine 1g/m2 IV over 2 hours on days 1-5 |
27 | Not reported | Median 64 years (range 21-80) for all patients including MDS |
Not reported | Mucositis, diarrhea, rash, nausea/vomiting, fever, infection |
44% CR |
| Weihrauch, 2004 [145] |
Topoisomerase I inhibitor | Topotecan | Cytarabine | Topotecan 1.25 mg/m2 cont IV per day on days 1-5 + cytarabine 1g/m2 IV over 2 hours on days 1-5 |
1 | Not reported | Median 62 years (range 32-75) for all patients including MDS |
Not reported | GI, rash, fever, alopecia, pain | Non-CR |
| Quintas- Cardama, 2006 [172] |
Topoisomerase I inhibitor | 9-Nitro- camptothecin |
None | 9-NC 2 mg/m2 PO daily × 5 d/wk as tolerated |
32 | 26 (81%) CMML-1, 5 (16%) CMML-2 |
Median 66 years | Diploid, trisomy 8, other reported for responders |
GI (reversible) | 40% ORR, 16% CR |
| Ribrag, 2003 [173] |
Topoisomerase I inhibitor | CPT-11 | None | CPT-11 200 mg/m2 IV every 2 weeks |
5 | Not reported | Median 71 years, including patients with MDS (range, 51-77) |
Not reported for individual CMML patients |
TLS with ARF, invasive fungal infection, GI |
1 patient with CMML had disappearance of pleural effusion, splenomegaly and monocytosis but BM blasts > 5% |
| Kantarjian, 2010 [148] |
Deoxycytidine analog | Sapacitabine | None | 75 mg PO BID × 7 days every 3-4 weeks |
Not reported |
Not reported | Median 65 years (range, 35-90), including all patients with CMML, AML, MDS, ALL |
Responders: del 13q, diploid, other (noncomplex) |
GI, alopecia, fatigue most common |
3 patients with h/o CMML responded; CMML→AML: CRp (2.2 mos); MDS- CMML: CR (3.3 mos); MDS-CMML: BM CR (2 mos) |
| Faderl, 2010 [149] |
Nucleoside analog | Clofarabine | None | After toxicity evaluations, 20 mg/m2 PO daily × 5 days, every 4-8 weeks |
6 | 5 (15%) CMML- 1, 1 (3%) CMML-2 |
Median 70 years (range, 53-86), including all patients with MDS, CMML, AML |
Not reported | GI, rash, elevated LFTs, fatigue, headache most common |
33% CR |
| Apperley, 2002 [37] |
Tyrosine kinase inhibitor | Imatinib | None | 400 mg PO daily | 3 adults, 1 child |
Not reported (PDGFRB subtype) |
6, 32, 50, and 68 years | All contained translocations involving Chr 5q33 |
No significant events reported | 100% CR |
| Magnusson, 2002 [38] |
Tyrosine kinase inhibitor | Imatinib | None | 400 mg PO daily | 1 | Not reported (PDGFRB subtype) |
29 years | t(5;17)(q33;p13.3) | None | 100% CR |
| Giles, 2003 [153] | Tyrosine kinase inhibitor | Semaxanib | None | 145 mg/m2 IV twice weekly | 6 | Not reported | Median 66 years (range, 29-85), including all patients with MPD, CMML, CML-BP, AMM |
Not reported | Abdominal pain, bone pain, dyspnea, headache, fatigue most common |
1 patient (17%) with stable disease >6 months |
| Strupp, 2002 [154] |
Immunomodulator | Thalidomide | None | 100-400 mg PO daily | 3 | Not reported | 59, 69, 73 years | Poor, good, and good IPSS risk cytogenetics |
Fatigue, obstipation, edema most common |
33% hematologic improvement, platelets |
| Raza, 2001 [155] | Immunomodulator | Thalidomide | None | 100-400 mg PO daily | 4 | Not reported | Median 67 years, including all patients with MDS and CMML |
Not reported for individual CMML patients |
Fatigue, constipation, dyspnea, edema, dizziness, rash, neuropathy, fever, headache, nausea |
0% response |
| Raza, 2006 [146] | Immunomodulator followed by topoisomerase I inhibitor |
Thalidomide | Topotecan | Topotecan 1.25 mg/m2 on days 1-5 of a 21-day cycle for 3 cycles, and then evaluated. If blasts were less than 5% or had decreased by more than 50%, the patients were then treated with thalidomide 100 mg/day (dose escalated up to 300 mg/day) for up to 1 year |
6 | Not reported | Median 68 years (range, 52-79), including patients with MDS |
46, X, Y, del(7) (q11.2) in responding patient |
Pain, fatigue, fever, constipation most common |
17% (1 patient) PR with hematologic improvement in erythroid cells |
| Bejanyan, 2011 [158] |
Immunomodulator + others | Thalidomide | Arsenic trioxide, dexamethasone, ascorbic acid |
TADA regimen: Thalidomide 50 mg/day × 2 weeks, then 100 mg/day × 6 months; ATO 0.25 mg/kg × 5 days, then 0.25 mg/kg twice per week × 11 weeks; Dex 4 mg/day × 5 days every 4 weeks; AA 1000 mg PO 2-3 hours prior to each ATO dose |
8 | All 8 had CMML-1 |
Median 66 years, including patients with MDS/MPN-u, PMF, and splenomegaly |
Not reported for individual CMML patients |
Fatigue, edema, cough, dyspnea, GI, neuropathy, infection, rash |
38% overall response (1 PR and 2 stable disease) |
| Raza, 2008 [157] | Immunomodulator + hypomethylator |
Thalidomide | 5-Azacytadine | 5-Azacytadine 75 mg/m2 SC daily × 5 days every 28 days + thalidomide 50-100 mg PO daily |
4 | Not reported | Median 72 years (range, 49-84), including patients with MDS, AML |
Diploid: 2 patients; 46,xy,r(18)(p11.3q23)[1 0]/46,xy[10] and 47,xx,18[13]/46,xx[7] in the other 2 |
Fever, DVT, GI, infection | 50% with major hematologic improvement (both in patients with diploid CGs) |
| Platzbecker, 2007 [159] |
Immunomodulator | Lenalidomide | None | 25 mg/day × 14 days | 1 | CMML-2 | 66 years | Single del(5q)(q31); FISH revealed loss of CSF1R gene at 5q33, and not EGR1 |
None reported | Hematologic improvement |
| Buckstein, 2014 [174] |
Immunomodulator | Lenalidomide | Melphalan | Lenalidomide 10 mg PO daily; Melphalan 2 mg PO daily for 21 days of a 28- day cycle |
12 | 10 (83%) CMML-1; 2 (17%) CMML- 2 |
Median 73 (range, 52- 87), including patients with MDS |
Not reported for individual CMML patients |
Infection, neurological | 25% overall response (1 CR, 1 HI-platelets, 1 HI-erythroid); all 3 responders had proliferative CMML-1 |
| Cambier, 1996 [175] |
Retinoid | All-trans retinoic acid |
+/− Hydroxyurea (for differentiation syndrome in 6 patients) |
45 mg/m2 daily | 10 | Not reported | Median 66 years (range 57-74) |
Not reported | Differentiation syndrome | 40% had reduction in transfusion requirement or increases in platelet count |
| Kuendgen, 2004 [160] |
Histone deacetylase inhibitor +/− retinoid |
Valproic acid | +/− ATRA | VPA administered PO with dose escalation to reach serum concentrations of 346-693 μM during months 1-4; ATRA 80 mg/m2 PO daily in 2 divided doses on days 1-7 every other week during months 3-4 |
1 | Not reported | 68 years | Normal | Vertigo, tremor | Progressive disease after 4 months |
| Siitonen, 2007 [161] |
Histone deacetylase inhibitor + retinoid |
Valproic acid | 13-cis retinoic acid + 1,25- dihydroxyvitamin D3 |
VPA administered PO with dose escalation to reach serum concentrations of 500-700 μmol/L; 13-cis retinoic acid 10 mg PO BID; VD3 1 μg PO daily |
4 | 3 (75%) CMML-1, 1 (25%) CMML- 2 |
73, 74, 76 years (CMML-1); 79 years (CMML-2) |
CMML-1 patients: normal; CMML-2 patient: t(1;3), +8 |
Cheilitis, dry skin, fatigue, elevated LFTs, pneumonitis |
CMML-2 patient had stable disease; CMML- 1 patients: 2 with stable disease and 1 with hematologic improvement |
| Voso, 2009 [162] | Histone deacetylase inhibitor + hypomethylator |
Valproic acid | 5-Azacytadine +/− ATRA |
VPA 600 to 1,500 mg PO on day 0 to reach a final plasma concentration of >50 μg/mL; then 5-AZA was added at a standard dose of 75 mg/m2 SC daily × 7 days every 4 weeks × 8 cycles. In cases of minor response, stable disease, or failure after four cycles, ATRA was added at 30 mg/m2 PO daily on days 8 to 27 × 4 cycles |
4 | Not reported | Median 70 years (range, 53-83) including patients with MDS |
Not reported for individual CMML patients |
Allergy, cardiovascular, GI, dyspnea, elevated LFTs |
Not reported for individual CMML patients. CR/PR rate for patients who completed 8 cycles (n=26) was 31%. |
| Ravoet, 2008 [176] |
Farnesyltransferase inhibitor |
Lonafarnib | None | 200 mg PO BID | 2 | Not reported | 63 and 77 years | Both normal | GI, fever, elevated LFTs | Both with stable disease |
| Feldman, 2008 [166] |
Farnesyltransferase inhibitor |
Lonafarnib | None | 200-300 mg PO BID | 35 | 11 were reported as MDS-CMML and 24 as MPD-CMML |
Median 70 years (range, 44-86) including patients with MDS |
Not reported for individual CMML patients |
GI, dyspnea, weakness, dehydration, fever, hypokalemia |
29% overall response (4 HI in MDS-CMML; 3 HI, 1 PR, 2 CR in MPD-CMML) |
| Kurzrock, 2003 [167] |
Farnesyltransferase inhibitor |
Tipifarnib | None | Increased from 300 mg PO BID on days 1-21 of a 28-day cycle |
10 | Not reported | Median 66 years (range 50-83), including patients with MDS |
Not reported for individual CMML patients |
Fatigue, rash, GI, elevated LFTs, bone pain |
30% in CMML patients (1 HI and 2 PR) |
| Fenaux, 2007 [170] |
Farnesyltransferase inhibitor |
Tipifarnib | None | Increased from 300 mg PO BID on days 1-21 of a 28 day cycle |
17 | 8 (47%) CMML-1, 9 (53%) CMML-2 |
Median 67 years (range 39-86), including patients with MDS |
Not reported for individual CMML patients |
Fever, infection, rash, fatigue | 18% CR (1 CMML- 1 and 2 CMML-2 patients); individual HI, PR for CMML patients not reported, but median survival for all CMML patients was 14.5 months |
| Borthakur, 2007 [177] |
Farnesyltransferase inhibitor |
FTS (s-trans, transfarnesylthiosalicylic acid) |
None | 200-600 mg PO BID on days 1-21 of a 28-day cycle |
1 | Not reported | Median 74 years (range 57-85), including patients with AML, MDS, and CML |
Not reported | Diarrhea | HI in CMML patient |
| Eghtedar, 2010 [178] |
JAK2 inhibitor | Ruxolitinib | None | 25 mg PO BID | 4 | Not reported | Median 69 years (range, 45–88), including patients with sAML, AML, ALL, MDS, and CML |
Not reported | Elevated LFTs | 75% (3 CMML patients) had clinical benefit; 1 of these (with JAK2 mutation) had reduction of BM blasts <5% |
molec, molecular; cont, continuous; IV, intravenously; 5/7, chromosome 5 or 7; GI, gastrointestinal; 9-NC, 9-Nitro-camptothecin; PO, orally; ORR, overall response rate; TLS, tumor lysis syndrome; ARF, acute renal failure; BID, twice daily; ALL, acute lymphocytic leukemia; del, deletion; h/o, history of; CRp, complete remission without recovery of platelets; LFTs, liver function tests; Chr, chromosome; AMM, agnogenic myeloid metaplaisia; IPSS, international prognostic scoring system for MDS risk; PR, partial remission; ATO, arsenic trioxide; Dex, dexamethasone; AA, ascorbic acid; MDS/MPN-u, MDS/MPN unclassifiable; PMF, primary myelofibrosis; SC, subcutaneously; DVT, deep venous thrombosis; CGs, cytogenetics; FISH, fluorescent in situ hybridization; ATRA, all-trans retinoic acid; VPA, valproic acid; VD3, 1,25-dihydroxyvitamin D3; 5-AZA, 5-azacytidine; HI, hematologic improvement; sAML, post-myeloproliferative disorder acute myeloid leukemia; CML, chronic myeloid leukemia.