Tefferi, Ayalew

e19538 Background: Chronic neutrophilic leukemia (CNL) is a rare and aggressive myeloproliferative neoplasm with poor survival. No standard of care exists. Case reports describe allogeneic stem cell transplantation (ASCT) as the only curative therapy. Using the National Cancer Database (NCDB), we studied prognostic factors and survival outcomes of CNL. Methods: Patients diagnosed in 2004-2015 were included. 9963/3 was the ICD-O-3 code. Overall survival (OS) was analyzed using the Kaplan-Meier method. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox proportional hazards model. Variables significant in univariate analysis were included in a multivariate analysis. Data on incidence was obtained from the Surveillance, Epidemiology, and End Results Program (SEER) 21 Registries (2004-2015). The analysis was done with SEER*Stat software. Incidence was age-adjusted to the U.S. 2000 standard population. Results: A total of 121 CNL patients were in NCDB. The median age at diagnosis was 70 years (range 21-90); 74 (61%) were males and 107 (88%) were ≥ 50 years. The median follow up time was 5.8 years (interquartile range [IQR] 2.9-7.4). 32 (26%) had a Charlson Deyo score (CDS) > 1. 80 (70%) had government insurance, while 34 (30%) had private insurance. Median OS was 2.2 years (IQR 0.8-6.7). OS was 70% at 1 year, 29% at 5 years, and 11% at 10 years. The year of diagnosis was not associated with improved OS (HR: 0.95 (95% CI: 0.88-1.02), p =0.14). 71 (59%) patients received chemotherapy. The median time to chemotherapy from the day of diagnosis was 15 days (IQR 7-35). The OS of those who received chemotherapy was 71% at 1 year and 27% at 5 years versus 69% and 32% at 1- and 5- years for those who did not ( p= 0.38). 2 patients received ASCT (age 52 and 61 years) as initial therapy and both were alive at 5 years. Factors predicting inferior OS on univariate analysis were age ≥ 50 years at diagnosis ( p= 0.005), male ( p< 0.001), CDS > 1 ( p= 0.038), and government insurance ( p= 0.004). The table shows the multivariate (MV) analysis. The overall incidence of CNL was 0.1 cases/1,000,000 individuals and did not change significantly from 2004-2015. The incidences by male, female, White, Black, and American Indian/Alaska Native were also 0.1 cases/1,000,000 individuals. Conclusions: OS and incidence of CNL have not changed over the years. Age ≥ 50 years, male gender, and use of government insurance predicted inferior OS. [Table: see text]

Abstract Background: Current dogma for the management of patients with PV dictates controlling erythrocytosis (to goal hematocrit levels of &lt;45% (males) or &lt;42%(females)) to decrease risks of thrombohemorrhagic complications. Control is achieved by either phlebotomy (through induction of iatrogenic iron deficiency), and/or direct myelosuppression (through hydroxyurea, interferon-alpha, or anagrelide). Although phlebotomy is clinically considered a very benign therapy, we hypothesize that PV associated fatigue is exacerbated by iron deficiency induced fatigue (Qual Life Res2000;9:5(491–7)), and evaluated the impact of therapeutic control of erythrocytosis on PV patients. Methods: A detailed analysis of patients with PV whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, current medications, current blood counts, frequency of phlebotomy, constitutional symptoms, and fatigue (FACT-An and Brief Fatigue Inventory). Results: A total of 405 self reported PV patients (median age 56; 48% female) from a wide geographic international distribution responded. Individuals were a median of 4 years from their initial diagnosis of PV (range 0–36). Prior PV associated complications were reported as thrombotic (n=98; 24%), hemorrhagic (n=101; 25%), or both events (n=37; 9%). When these latter values were combined with age (i.e. &gt;60 years) 61% of patients (n=246) would be considered high risk. Therapy for their PV was reported by 96% (n=388) patients, with 89% (361) having been phlebotomized, 72% (n = 291) received aspirin, 64% (n = 261) having received 1 or more myelosuppressive agent (hydroxyurea 53% (n = 216), anagrelide 22% (n = 88), interferon-alpha 16% (n = 63)). Amongst patients whom were phlebotomized over the past year (43%; n =174: median 4 units (range 1–18)), 53% (n = 92) received concurrent myelosuppressive therapy. Amongst patients whom originally, but no longer required phlebotomy 35% (n = 142), 94% (n = 134) were receiving myelosuppressive treatments. QOL assessments indicated fatigue as measured by both instruments is clearly increased across the PV respondents compared to published controls for those instruments (p&lt;0.001). Additionally, although the burden of fatigue was not significantly higher in “high-risk” PV, fatigue levels were higher amongst those with prior thrombo-hemorrhagic events (p=0.03, or both types of events p&lt;0.01). In regards to the impact of PV therapy upon fatigue, the burden of this symptom was not significantly diminished for those individuals on phlebotomy alone compared to those on cytoreductive therapy. Neither did fatigue levels correlate with the frequency or intensity of phlebotomy. Additionally, although fatigue burden was high (compared to controls) amongst patients on cytoreductive therapy, no agent had a clear advantage in alleviating (or disadvantage in exacerbating) fatigue. Conclusions: Fatigue amongst patients with PV is significantly increased compared to controls, and no therapeutic option seems to have a significant advantage with regards to fatigue. Given the multifactorial and subjective nature of fatigue it is impossible to separate the individual contributions of disease activity and therapy to the burden of fatigue in these patients. Hopefully, targeted therapy against the molecular origins of myeloproliferation in these patients will lead to better improvements in fatigue than current options offer.

Abstract Background: We recently reported on MPLW515L/K mutations in 1182 patients with myeloid disorders (Blood, First Edition July 25, 2006) and found low frequency occurrence in in agnogenic myeloid metaplasia (AMM) (~5%) and essential thrombocythemia (ET) (~1%), but not polycythemia vera (PV). Of the 20 MPLW515L/K-positive patients in that series, 6 (30%) also carried a low burden of the JAK2V617F mutation. Studies of mutation prevalence in individuals with clonal granulopoiesis as well as familial myeloproliferative disorders (MPD) studies suggest that these mutations (JAK2V617F) may be acquired as secondary genetic events. Aim: to gain additional insight regarding the aforementioned two mutations and MPD pathogenesis by determining (i) concordance between mutation expression and clonal hematopoiesis, (ii) the instructive role of each mutation in determining lineage fate, iii) differences in pattern and lineage restriction of these mutations between various MPD, and (iv) chronology of clonal emergence and clonal dominance for the 2 mutations. Methods: Sixteen MPD patients were studied (13 JAK2V617F+ and 3 MPLW515L/K+); 9 had PV (all JAK2V617F+), 2 ET (both JAK2V617F+), 1 CMML (JAK2V617F+), and 4 AMM (2 MPLW515K+, and one each with MPLW515L and JAK2V617F). CD34+ progenitor cells were plated in methylcellulose and resulting hematopoietic colonies were scored on day 10–12. Colonies were obtained with (all patients) and without (10 patients; 5 with PV, 1 ET, and 4 AMM) cytokine support. Individual colonies were screened for presence of either mutation by DNA sequencing. In addition, MPLW515L/K analysis was performed in T and B lymphocytes in 3 informative cases. Finally, serially stored bone marrow was examined in 3 patients with co-expression of MPL515 and JAK2V617F mutations. Results: A total of 552 hematopoietic colonies from 16 MPD patients were genotyped. We found cohabitation of both mutation-positive and mutation-negative endogenous colonies in PV as well as other MPD. For JAK2V617F+ patients, the majority (75–100%) of erythropoietin-independent erythroid colonies (EEC) but not endogenous granulocyte colonies (20–70%) were mutation-positive. In contrast, no EEC were obtained from progenitors from the 3 MPLW515L/K+ patients. For 2 of the 3 patients, the endogenous myeloid colonies were predominantly mutation-positive (~90%). A mixed allele pattern (homozygous and/or heterozygous) was seen with both mutations regardless of MPD phenotype, but the overall mutant colony burden was higher with MPLW515L/K mutations relative to JAK2V617F. When such testing was possible, MPL515 mutations were detected in T-lymphocytes (2 of 3 patients) as well as B-lymphocytes (2 of 2 patients). Finally, among 3 patients carrying both mutations, serial marrow studies (25 time points over 4–8 years) revealed the occurrence of both mutations at diagnosis and persistent dominance of MPLW515L/K over JAK2V617F over time. Conclusions: Our observations provide direct evidence for clonal hematopoiesis that antedates acquisition of either MPLW515L/K or JAK2V617F that bias towards myeloid and erythroid fates, respectively. Furthermore, both mutations appear to occur early in the disease course and lineage studies suggest a hierarchically earlier stem cell origin for MPLW515L/K as compared to JAK2V617F.

Abstract Background: We had previously piloted thalidomide treatment in MMM and showed an approximately 20% response in terms of both anemia and splenomegaly (Elliott et al. BJH2002;117:288). Encouraged by this experience, we undertook the current phase II study to explore the therapeutic activity of the more potent as well as less neurotoxic immunomodulatory drug, lenalidomide (CC-5013). Methods: The study group comprised a consecutive series of patients with MMM that fulfilled protocol entry criteria that included hemoglobin level ≤ 10 g/dL, platelet count ≥ 100 x 109/L, and neutrophil count ≥ 1 x 109/L. The treatment program consisted of daily oral lenalidomide (10 mg/day) for 3 consecutive 28-day cycles with a plan to continue with additional 3 cycles in case of response. Results: i. Pretreatment patient information Twenty-seven patients (median age, 66 years; range, 40–78) were accrued between March 5, 2004 and June 15, 2005. Median duration of disease prior to protocol treatment was 30 months (range, 1–245). Previous therapy was documented in all but 2 patients. Twenty patients were RBC transfusion-dependent. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were 16 cm (0–31), 8.4 x 109/L (1.8–84.4), 299 x 109/L (124–831), 166.1 x 106/L (2.8–5176.4), and 778 U/L (267–1725), respectively. Cytogenetic abnormalities were detected in 13 patients (48%). JAK2 V617F mutation analysis was performed in 21 patients and revealed homozygous, heterozygous, and wild-type alleles in 3, 8, and 10 patients, respectively. ii. Adverse events Adverse events (any/grade 3 or 4) with definite, probable, or possible attributions to the drug included fatigue (52%/12%), neutropenia (40%/24%), pruritus (36%/0%), thrombocytopenia (28%/8%), anemia (16%/8%), rash (12%/8%), and respiratory distress with hypoxia (8%/8%). To date, 7 deaths have been reported, all occuring after discontinuation of protocol therapy, and none were directly linked to the drug. iii. Response The median post-treatment follow up is now 16 months (range 1–17 months). During this period, 6 patients (22%) have experienced either a major (3 patients normalized their hemoglobin level), minor (2 patients became transfusion-independent), or marginal response in anemia. The median time to response and response duration were 2 and 7 months, respectively. Two of the 3 major responders had a baseline der(1;18)(q10;q10) or del(5)(q13q33) cytogenetic abnormality, the latter one of which displayed a major cytogenetic remission. In the patient with der(1;18)(q10;q10), the hemoglobin level increased to a level of 19.1 g/dL from being transfusion-dependent at the start of lenalidomide therapy. Interestingly, the particular patient was homozygous for the JAK2 V617F mutation. Responses were also recorded for palpable splenomegaly (26%), constitutional symptoms (67%), and serum LDH level (70%). Seven patients normalized their LDH. Conclusion: Lenalidomide therapy improved anemia in at least 20% of patients with MMM. Some of the responses were spectacular and appeared to be associated with specific cytogenetic abnormalities. The documentation of a positive drug effect on LDH, constitutional symptoms, and splenomegaly in patients not showing early response in anemia suggests the possibility of an even higher response rate with a longer treatment schedule.

Abstract Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms. Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)). Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below. Phenotypic Variability Amongst 458 MMM Patients Category AMM (N=148; 32.3%) PPMM (N=174; 38.0%) PTMM (N=136; 29.7%) MMM Total (N=458) Δ between groups (p = ) Hb = Hemoglobin; SCT = Stem Cell Transplant Age (Median) 61 57 57 58 0.09 Sex (% Males) 60% 49% 30% 47% &lt;0.01 Yrs from MPD Dx 5 6 8 6 &lt;0.01 Labs/ Prior History Hb (g/dL) 11.0 13.7 11.6 12.1 &lt;0.01 % with RBC Tx 43% 6% 11% 20% &lt;0.01 Leukocytes (×10(9)/L) 8.0 7.6 7.2 7.7 0.64 Platelets (×10(9))/L) 200 352 396 321 &lt;0.01 % with Splenomegaly 76% 49% 41% 54% &lt;0.01 % with Prior Thrombosis 10% 22% 31% 21% &lt;0.01 % with Prior Bleed 16% 20% 31% 22% 0.01 Treatment History for the MMM % with Prior Tx for MPD 64% 88% 77% 77% &lt;0.01 % Medical Therapy 57% 70% 75% 67% &lt;0.01 # Meds (Median (Range)) 1 (0–8) 2 (0–6) 2 (0–6) 2 (0–8) &lt;0.01 % with Splenectomy 8% 5% 6% 6% 0.48 % with SCT 6% 1% 1% 3% &lt;0.01 MMM Associated Constitutional Symptoms % with Fatigue 85% 81% 85% 84% 0.56 % with Bone Pain 51% 46% 44% 47% 0.51 % with Fevers 19% 17% 18% 18% 0.87 % with Pruritus 39% 69% 39% 50% &lt;0.01 % with Night Sweats 55% 58% 53% 56% 0.67 % with Weight Loss 30% 15% 16% 20% &lt;0.01 Overall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P&lt;0.0001) yet there was no difference between MMM subtypes for the severity of fatigue. Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.

Abstract Background: Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance of these two scenarios. Methods: The study population consisted of 65 (47.7% female) consecutive, newly diagnosed CML patients seen at the Mayo Clinic with a median age of 59 years. 44.5 percent were initially treated with interferon alpha (IFN) resulting in complete cytogenetic remission in 10.7 percent for a median length of 5.83 years, partial cytogenetic remission in 3.57 percent for a median length of 2 years. 55.5 percent were treated with imatinib (Gleevec) resulting in complete cytogenetic remission in 54.1 percent for a median length of 3.08 years, partial cytogenetic remission in 13.5% for a median length of 1.08 years. Results: Survival at five years through Kaplan-Meier analysis was approximately 92 percent in patients demonstrating only the Ph chromosome (n = 53), versus 60 percent in patients with additional chromosomal abnormalities (n = 12; p &lt; 0.0001 by both Logrank and Breslow-Gehan-Wilcox analysis). Furthermore, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, five year survival of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared to 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = 0.01 by Logrank and p = 0.001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = 0.05). Conclusion: Although it is tempting to speculate the possibility that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study. Figure Figure Figure Figure