CMML Cases Research Articles

Development and Validation of a New Prognostic Model for Myelodysplastic Syndrome (MDS) That Accounts for Events Not Considered by the International Prognostic Scoring System (IPSS)

Background. The IPSS risk model provides survival projections for patients with de novo MDS managed with supportive measures alone. For patients receiving investigational treatment, a prognostic stratification model is needed that can be applied at intervals after diagnosis and that adjusts for the impact of prior therapy, secondary forms of disease, proliferative CMML, and adverse cytogenetic subsets (e.g. 3 abnormalities, chromosome 7 abnormalities).Aims. To develop a new MDS risk model that accounts for subsets not included in IPSS, that refines prognostic subsets, and that applies at any time during course of MDS.Study Group. We analyzed 1915 patients with MDS referred from 1993 to 2005 (including CMML, secondary MDS, MDS with prior therapy). Only 507 patients (26%) had primary MDS without prior therapy (i.e. categorizable by IPSS). Patients were randomly divided into a study group (n=958) and a test group (n=957).Results. A multivariate analysis of prognostic factors in the study group identified the following adverse independent factors as continuous and categorical values (p<0.001), which were given weighted points based on coefficient (score point = coefficient: 0.15). This is shown in Table 1. Cutoffs for anemia, thrombocytopenia and blasts, and cytogenetic subsets, were different for IPSS. The new MDS prognostic model divided patients into four prognostic groups with significantly different outcomes, shown in Table 2. The model was validated in the test group with excellent segregation (Table 2). It was also highly prognostic in the 507 patients with newly diagnosed MDS (as per the original IPSS groups): median survivals 4.7, 3.0, 1.2, 0.75 years. Applying the prognostic score of the new model within the four IPSS risk groups, overall and in primary MDS without prior therapy, was highly prognostic in each. Applying IPSS within each of the 4 risk groups of the new MDS model was not prognostic. The model was also prognostic for multiple MDS subsets tested (Table 3). The new model accounts for duration of MDS and prior therapy. It is applicable to any patient with MDS at any time during the course of MDS. The new risk model was also tested in the 3 arm decitabine trial (n = 124); these patients were divided by the new model into 5 (4%) low risk, 21 (17%) Intermediate 1, 45 (30%) Intermediate 2, and 53 (43%) high risk. This indicates the worse prognosis in this study group (higher risk MDS 79%) The respective median survivals were: not reached (100% at 3 years), 42, 19, and 13 months, respectively (Table 3). This indicated the applicability of the model in a different MDS study group and suggested a better survival than expected (therapy effect?). To verify this, a cumulative score for the 124 patients was calculated and an average score deducted, which was associated with a predicted historical median survival of 13 months overall, 30 months for low-Intermediate 1 and 10 months for Intermediate 2-high risk, versus median survivals of 20 months overall, 44 months for low-Intermediate 1, and 15 months for Intermediate 2-high.Conclusions. A new prognostic model was developed and validated for MDS, which accounts for all MDS or CMML cases, regardless of prior therapy. The model has been validated in an independent test group and was shown to be superior to IPSS. It was also used to demonstrate an improved survival with decitabine compared with the expected (historical) survival by the new risk model. Further validations are needed in independent MDS populations.Table 1Prognostic factorCoefficientPointsPerformance status≥20.2672Age (in years)60–640.1791≥ 650.3362Platelets (× 109/L)<300.418330–490.270250–1990.1841Hemoglobin (g/dL)<12.00.2742Marrow blast %5–100.222111–290.2602WBC (× 109/L)>200.2582KaryotypeChromosome 7 abnormality or complex ≥ 3 abnormalities0.4793Prior transfusionYes0.1071Table 2SurvivalStudy GroupTest GroupRiskScoreNo. Pts (%)Median (Mos)3-year %No. PtsMedian (Mos)3-year %Low0 – 4157(16)54631594558Intermediate 15 – 6229(24)25342282335Intermediate 27 –8233(24)14162441315High≥ 9341(36)6432663Table 3Median Survival (Mo)/1-yr Survival % by new MDS ModelDisease*LowIntermediate 1Intermediate 2HighCMML (n=176)3319128MDS – prior therapy (n=702)3819128Secondary MDS (n=571)4319166Decitabine trial (3-arm – n=124)Not reached -100% at 3-yr421913Post decitabine failure (n=59) (% 1 yr surv)100%54%41%18%

Lack of correlation of eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients with myeloproliferative disorders, myelodysplastic syndromes, acute leukemias or aplastic anemia with long-term treatment

7092 Background: PNH is a rare disorder characterized by bone marrow dysfunction and expansion of stem cell clones with somatic mutations in the PIG-A gene. Mutations in PIG-A result in deficiency of GPI-anchored proteins on the surface of blood cells including the complement inhibitor CD59. Lack of CD59 from PNH RBCs results in chronic hemolysis and leads to fatigue, thrombosis, anemia and poor quality of life. Development of myeloproliferative disorders, MDS, acute leukemias and AA/pancytopenia has been reported in PNH. In a previous retrospective analysis, 6.8% of patients developed either myeloid or lymphoid disorders and 1% developed acute leukemias. AA/pancytopenia has been reported to develop in PNH patients at a rate of ∼2%/year. Eculizumab prevents terminal complement activation and restores the PNH RBC clone resulting in improvements in anemia, thrombosis, fatigue, and quality of life. Eculizumab has been evaluated in 195 PNH patients initially enrolled in 1 of 3 parent trials who continued to receive drug in an extension trial (>382 patient years of exposure). Methods: Cell counts for RBCs, WBCs, platelets and neutrophils and leukocyte PNH clone size were assessed at baseline and at 18 mos. The frequency of MDS, leukemia and AA/pancytopenia was calculated across all eculizumab trials. Results: RBC, WBC, platelet and neutrophil counts did not change during 18 mos of eculizumab. PNH leukocyte clone size did not increase with eculizumab (median 96.7% at baseline vs 96.7% at 18 mos) suggesting that inhibition of complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the development of MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The case of CMML was attributed to a previously diagnosed high grade myelodysplasia. Interestingly, no new AA/pancytopenia cases developed during eculizumab, while 7–8 cases would have been expected from the reported rate. Conclusions: Long-term terminal complement inhibition with eculizumab does not increase myeloproliferative disorders, MDS, acute leukemias or AA/pancytopenia in PNH patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals

Secondary chronic myelomonocytic leukemia with monosomy 7 after successful treatment of acute promyelocytic leukemia

Current APL chemotherapy protocols usually include high-dose anthracyclines, mitoxantrone, and epipodophillotoxins, which are topoisomerase II inhibitors of high leukemogenic potential. In the last years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL have been made. We report herein a first case of CMML with monosomy 7 occurring after treatment of APL.

Clinical Trials Underestimate Age of Chronic Myeloid Leukemia (CML) Patients: Epidemiological Study in a Representative Area in Germany.

Epidemiological information on chronic myeloproliferative disorders (CMPD), notably Philadelphia (Ph) and/or bcr/abl positive chronic myeloid leukemia (CML), is rare. National cancer registries and clinical trials differ with regard to median age of CML patients by 10 to 20 years (Table). Therefore, an evaluation was conducted in a defined area in Germany between 1998 and 2000 to determine incidences and compare clinical characteristics of Ph and/or bcr/abl positive CML patients participating and not participating in trials. 68 (37.4%) hospitals and 241 specialty practices (16.4%) reported 893 newly diagnosed CMPD patients. CML patients represented 24.9% of all cases with CMPD. The crude incidence of CML cases (n=218) was 0.79, that of the 172 Ph and/or bcr/abl positive CML cases 0.62 and that of CMML (n=61) 0.22. The incidence of CML and CMML cases combined was 1.01. 110 (64.0%) of the 172 Ph and/or bcr/abl positive CML patients participated in clinical studies, mainly CML Studies III and IIIA of the German CML Study Group. Median age was significantly different between patients participating and not participating in clinical trials: (54.1 vs. 64.8 years, p=0.0001). The chance for a Ph and/or bcr/abl positive CML patient < 65 years to be enrolled in a clinical study was 3.8 times higher than for a CML patient ≥ 65 years (OR=3.8, CI: 1.9–7.3). Male patients had a slightly higher probability to be enrolled in a study than females (OR=1.5 (CI: 0.8–2.8)). Our data indicate that 36% of the Ph and/or bcr/abl positive CML patients registered in a defined area of Germany are not treated in clinical trials, that elderly patients have a lower probability to be included in trials than younger patients and that patients participating in trials are 10.7 years younger than those who do not.Age of CML Patients in Population based Registries and in Clinical TrialsA) RegistriesAge mean (years ± S.D.) /Thames Cancer Registry, U.K.65 (20–98)SEER Cancer Statistics Review, 1975–200468 (range not available)SEER cancer statistics review, 1973–199864 (range not available)B) TrialsThe Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 199448 ± 14Hehlmann et al., Blood 199448 (17–85)Guilhot et al., N Engl J Med 199750 (7–70)Hasford et al., JNCI 199849 (10–85)The Benelux CML Study Group. Blood 199856 (20–83)Baccarani et al., Blood 200245 ± 13Hehlmann et al., Leukemia 200348 (10–83)O'Brien et al., N Engl J Med 200350 (18–70)Hehlmann et al., Blood 200749 (11–90)

Evaluation of risk for development of myeloproliferative disorders, myelodysplastic syndromes, or acute leukemias with long-term eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients

7087 Background: PNH is a rare bone marrow failure disorder defined by stem cell clones with somatic mutations in the PIG-A gene. These mutations result in peripheral blood cells deficient in GPI-anchored proteins including complement inhibitors CD55 and CD59. Chronic lysis of PNH RBCs leads to severe anemia, life-threatening thrombosis, debilitating fatigue, and impaired quality of life. Previous studies have indicated an increased frequency of myeloproliferative disorders, MDS, and acute leukemias in PNH. In a previous retrospective analysis of 1,760 PNH patients, 6.8% developed either myeloid or lymphoid disorders and 1% developed acute leukemias. Eculizumab (Soliris) is a humanized antibody that prevents terminal complement activation. Long-term eculizumab treatment has been evaluated in 195 PNH patients (&gt;250 patient years of exposure) and shown to significantly restore the endogenous PNH RBC clone resulting in improved anemia, as well as significant improvements in thrombosis, fatigue, and quality of life. Methods: Leukocyte clone sizes were assessed at baseline and 26 weeks for patients receiving eculizumab in the Phase III clinical trials (TRIUMPH and SHEPHERD) using flow cytometry. The frequency of MDS and leukemia was calculated as a percentage of the eculizumab-treated patients across all eculizumab trials. Results: PNH leukocyte clone size did not increase with eculizumab treatment (median 96.1% at baseline vs 95.5% at week 26; P=0.80, signed rank test) suggesting that inhibition of terminal complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the frequency of new MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The single case of CMML occurred in a patient previously diagnosed with and was attributed to high grade myelodysplasia. Conclusions: To date, eculizumab treatment of PNH patients does not increase the risk for the development of myeloproliferative disorders, MDS or acute leukemias. Patients on eculizumab will continue to be followed in a Global PNH Safety Registry. No significant financial relationships to disclose.

Presence of JAK2 Mutations in MDS/MPD-u WHO Classified Patients and Not Other Forms of MDS Suggests Their Derivation from Classical Myeloproliferative Syndrome.

The WHO classification of myeloid neoplasms recognizes a category of myeloid disorders that overlaps traditional myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) as the entity MDS/MPD disease. This disease category includes CMML, JMML, atypical CML and MDS/MPD unclassifiable (MDS/MPD-u). The provisional entity termed RARS associated with marked thrombocytosis (RARS-t) is currently best classified as MDS/MPD-u until further information is available regarding its pathogenesis. Recently a JAK2 mutation V617F (G→T) was identified as a pathogenetic lesion in typical myeloproliferative disorders (Kralovics et al, NEJM , 2005). Subsequent studies of the JAK2 mutation concentrated on more proliferative forms of MDS or MDS/MPD such as CMML and CNL (Steensma et al, Blood , 2005). These studies demonstrated that homo- and heterozygous JAK2 mutants are present in a rather small proportion of these patients. Based on similar clinical features, we theorized that JAK2 mutants might be also found in patients with MDS/MPD-u. We have collected a cohort of these patients (N=202) and analyzed them for the presence of JAK2 mutation using a molecular allele-specific PCR assay. Positive cases were confirmed by sequencing with a sensitivity of about 20% of mutated cells. A group of patients with PV, MF and ET served as positive controls (N=66). In agreement with previous reports, the detection rate of JAK2 mutants for PV, MF and ET was 92%, 55% and 55%, respectively. Our experimental group included 104 patients with MDS or MDS/MPD (53 RA/RS, 14 RAEB, 22 RAEB-t/sAML, and 15 CMML). Most significantly, the RA/RS group contained 13 patients with WHO-defined MDS/MPD overlap and 3 with RARS-t (among these patients, 3 were JAK2 mutants; all of them were heterozygous - 18.8%). Within 16 patients with CMML1 or 2 we found only 2 heterozygous for JAK2 mutation (12.5%). The remaining cohort of 73 patients in MDS categories revealed only 1 patient to be heterozygous for JAK2 mutation (RARS, 1.4%). As expected MDS/MPD patients with JAK2 mutation showed various degrees of BM fibrosis, splenomegaly and less pronounced cytopenias. Except for one patient, JAK2 mutants had normal cytogenetics. All had normal MCV and ANC. In 4/5 increased megakaryocytes with/or without atypia was seen. One CMML patient with abnormal cytogenetics showed an unusual translocation t(8;9)(q22;p24). JAK2 is located at 9p24 so it is possible that the JAK2 gene was involved in the translocation generating a novel fusion protein in addition to an activating JAK2 mutant. Our results showed that JAK2 mutations are rarely found in typical cases of MDS or CMML. However, further analysis of JAK2 mutational status in patients with MDS/MPD-u is warranted. The reported detection rate may suggest that the pathogenesis of these entities is more akin to myeloproliferative than myelodysplastic syndromes.

Myelodysplastic syndrome at a large tertiary care community hospital: analysis according to the international prognostic scoring system

The outcome of patients diagnosed with primary myelodysplastic syndromes (MDS) between 1990 and 1997 from William Beaumont Hospital (WBH) was analyzed according to the International Prognostic Scoring System (IPSS) risk categorization. A retrospective study of 195 MDS patients was performed. Seventy-nine patients with MDS, in whom a karyotype was obtained and with an adequate follow-up were included in the final analysis. Cases of proliferative CMML (WBC >12×10 9/l) were excluded from the study. The overall median survival was 3.1 years, and median survival stratified by IPSS was 3.4, 4.1 and 0.5 years for the INT-1, INT-2 and high risk group and not yet reached for the low risk group. The overall survival by IPSS subcategorization were 6.88, 5.29, 5.30 and 2.12 years for the low, INT-1, INT-2, and high risk groups respectively. Cytogenetics were significant in predicting the overall survival. The IPSS score stratified patients into risk categories for development of AML. The risk of development into AML was 8, 8, 33 and 54% for the low, INT-1, INT-2 and high risk groups, respectively. We conclude that IPSS score can be useful in predicting survival and AML evolution in some MDS patients.

Methylation status within exon 3 of the c- myc gene as a prognostic marker in myeloma and leukaemia

The third exon of the c- myc gene contains a CpG site which has been implicated as a regulatory region. When this site is methylated it has protein binding properties and binds a different set of proteins in normal and neoplastic cells. Recent work using myeloma cell lines indicates a correlation between hypomethylation at this site and enhanced expression of the myc protein. We investigated the methylation status of this site in 10 cases of myeloma but found that there was no change from the high degree of methylation found in normal cells. Therefore, methylation status at this site is unlikely to serve as a prognosticator in myelomatosis. However, methylation changes at this site were observed in DNA from two cases of CMML, in which hypomethylation was observed and in three AML cases, which were completely methylated at this site.

Cytogenetics of chronic myelomonocytic leukemia

In a retrospective multicenter study by the Groupe Français de Cytogénétique Hématologique, chromosome investigation was undertaken in 120 cases of chronic myelomonocytic leukemia, which was diagnosed in accordance with the French-American-British (FAB) criteria. Chromosome abnormalities of the clonal type were present at diagnosis in 30% of the patients. Median age of these patients was lower than for these without karyotypic abnormalities, and prognosis was less favorable. The most frequently encountered characteristic chromosome change was monosomy 7; chronic myelomonocytic leukemia (CMLL) with monosomy 7 occurs in younger age groups and has a very poor prognosis. Next in frequency were trisomy 8, iso(17q), and a 12p anomaly. The latter may have to be classified among the so-called primary characteristic chromosome changes in leukemia. All chromosome changes were of the type usually found in myeloid proliferation, and no anomaly specific for CMML was discovered. Isochromosome 17q was found only during blastic phase. Several of the CMML cases with chromosome anomalies were secondary leukemias, and among these was one case with a homogeneously staining region (HSR), which is rarely reported in leukemia. A paraproteinemia was found in 12% of the patients. No correlation of its occurrence with presence or type of karyotypic anomaly could be found.