ASH 2010 meeting report—Top 10 clinically‐oriented abstracts in myeloproliferative neoplasms
Authors: Ayalew Tefferi
Journal: American Journal of Hematology (2010)

The 2010 American Society of Hematology (ASH) annual meeting took place on December 4–7, 2010, in Orlando, Florida, USA. Over 20,000 people attended the meeting and more than 4,000 scientific abstracts were presented at oral or poster sessions. Among the latter, about 100 were in the category of BCR-ABL1-negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), and eosinophilic disorders. Here, I summarize and discuss the top 10 MPN abstracts, which I believe contain information that is immediately relevant to clinical practice. All 10 abstracts are published in full in the November 19, 2010 issue of Blood (volume 116, Issue 21) and are identified here by their abstract numbers. Pardanani et al. [1] presented the results of a Phase-1 study using oral CYT387, a JAK1/2 inhibitor, in patients with PMF or post-PV/ET MF. Thirty-six patients were enrolled and the study is currently ongoing with a target accrual of 140 patients. Twenty (56%) patients were red cell transfusion-dependent at study entry. The median treatment duration was 15 weeks (range 4–38). Dose-limiting toxicity (DLT) was established at 400 mg day−1; two of six subjects experienced either asymptomatic Grade 3 hyperlipasemia or Grade 3 headache. Maximum tolerated dose (MTD) was declared at 300 mg day−1. Both 300 and 150 mg day−1 doses were used in the dose-confirmation phase. Grade 3/4 non-hematologic adverse events (AEs) were infrequent; Grade 3 increases in transaminases, alkaline phosphatase or lipase were each seen in less than three patients. Thirteen (36%) patients experienced “first-dose effect” characterized by Grade 1 lightheadedness and hypotension; this phenomenon was self-limited and generally resolved within 3–4 hr with rare recurrence. Grade 3/4 thrombocytopenia was seen in 8 (22%) subjects, and treatment-emergent Grade 3 anemia in 1 (3%). Twenty two patients were evaluable for anemia response; of these, 9 (41%) achieved response per the International Working Group for MPN Research and Treatment (IWG-MRT) criteria. An even higher percentage of patients became transfusion-independent that lasted for a minimum of 12 weeks. Twenty nine subjects (97%) experienced reduction in spleen size, which was >50% in 11 (37%) patients. The drug was also effective in controlling constitutional symptoms, including pruritus, in the majority of patients. Treatment responses were also seen in patients who previously failed treatment with pomalidomide [2] or other JAK inhibitors such as INCB018424 [3] or TG101348 [4]. Anemia response was not affected by the presence of JAK2V617F and the drug did not significantly alter mutant allele burden. CYT387 is the first JAK inhibitor demonstrating substantial activity against MF-associated anemia. This represents a major development because anemia is the chief determinant of quality of life (QoL) in this disease and is also the most important prognostic factor for survival, [5-7] especially in the context of transfusion-dependent anemia [8]. CYT387 was also effective in alleviating both splenomegaly and constitutional symptoms and, in this regard, it appears to perform as well as INCB018424 [3] or TG101348 [4]. Obviously, these preliminary observations need to be validated in a larger group of patients and longer follow-up is needed to better appreciate the drug's safety and durability of response. Barbui et al. [9] present an international study of 1,104 patients previously diagnosed and treated as ET. Revision of the BM biopsies according to the WHO morphological criteria confirmed ET in 891 patients (81%). Diagnosis was revised to early, prefibrotic PMF in 180 patients (16%). Early PMF, as opposed to ET, was characterized by higher leukocyte (P < 0.0001) and platelet (P = 0.002) counts, lower hemoglobin (P = 0.01), higher serum LDH level (P < 0.0001), higher circulating CD34+ cell count (P = 0.03), and more frequent palpable splenomegaly. Patients with early PMF, as compared to those with ET, were more likely to develop overt myelofibrosis or acute leukemia. Cumulative leukemic transformation rate at 10 and 15 years was 0.7 and 2.1% in ET versus 5.8 and 11.7% in early/prefibrotic PMF. The 10- and 15-year overall survival rates were 89 and 80% in ET versus 76 and 59% in early/prefibrotic PMF. On multivariable analysis, other risk factors for poor survival were age >60 years, a leukocyte count of >11 × 109/L and history of thrombosis. JAK2V617F mutational frequency (60%) and thrombotic events were similar between the two groups. This study has a major impact on current clinical practice. First, it validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET [10]. Second, it confirms our long-held impression that WHO-defined ET is a relatively indolent disease with near-normal life expectancy and a less than 1% risk of leukemic or fibrotic transformation in the first 10 years of disease. This is not a trivial matter because it underscores the need to be careful when it comes to introducing (or endorsing) new drugs for the treatment of ET; history has taught us that our patients might pay the price for our lack of critical judgment [11]. Finally, the current study provides new information on the survival and risk of leukemic transformation in prefibrotic PMF [12]. Begna et al. [2] presented results from a Phase-2 study using single agent low-dose (0.5 mg day−1) pomalidomide in anemic patients with MF. The main eligibility criterion was transfusion-dependence or hemoglobin <10 g dL−1; subjects failing previous treatment with lenalidomide or thalidomide were eligible. Fifty-eight patients were included in the study, among whom 46 (79%) were transfusion-dependent and 42 (72%), JAK2V617F-positive. Treatment was well-tolerated with no instances of thrombosis. There was Grade 1 neuropathy possibly related to drug in one subject. Grade 3 thrombocytopenia/neutropenia occurred in two subjects. Anemia response, per IWG-MRT criteria, was seen in 10 (17%) subjects including 9 who became transfusion-independent. In addition, 14 of 24 patients (58%) with platelets <100 × 109/L had a >50% increment in their platelet count. There were no spleen responses. Anemia response occurred only in the presence of JAK2V617F (24% vs. 0%; P = 0.03). Anemia response in JAK2V617F-positive subjects was predicted by the presence of pomalidomide-induced basophilia in the 1st month of therapy (38% vs. 6%; P = 0.02) or absence of marked splenomegaly (38% vs. 11%; P = 0.05); response was not affected by cytogenetic risk-category. I believe that pomalidomide will be a valuable treatment option for anemia in JAK2V617F-positive patients with MF, in the absence of marked splenomegaly [13, 14]. More than a third of such patients can achieve anemia response that includes becoming transfusion-independent. Drug-induced basophilia in the first month of treatment predicts subsequent anemia response. Pomalidomide has limited value in the treatment of MF-associated splenomegaly but might be of benefit in some patients with thrombocytopenia. I am most impressed by its excellent safety profile. Verstovsek et al. [15] presented longer-term follow-up of an ongoing trial of oral INCB018424 (JAK1/2 inhibitor), in hydroxyurea-refractory or intolerant PV or ET. Starting doses were 10 and 25 mg BID. The study included 34 PV patients followed for a median of 15 months. As expected almost all (97%) patients became phlebotomy-independent. A greater than 50% reduction in spleen size was achieved in 59% of patients. Leukocytosis or thrombocytosis resolved in 63 and 69% of patients, respectively. Six (18%) patients discontinued therapy. Seven Grade 3 AEs were reported and included thrombocytopenia and neutropenia. A total of 39 ET patients were enrolled and followed for a median of 15 months. Normalization of platelet count occurred in 49% of these patients after a median of 2 weeks. Nine (23%) patients discontinued therapy. Grade 3 AEs included leukopenia in two patients and peripheral neuropathy in one. As expected, the drug controlled pruritus and other constitutional symptoms in the majority of patients. Only 6% of PV and 12% of ET patients experienced a >50% decrease in JAK2V617F allele burden. PV or ET patients who are either intolerant or resistant to hydroxyurea are effectively managed by INF-α [16, 17], busulfan [18, 19], or pipobroman (not available in the US) [20-23]. Among these second-line drugs, I prefer the use of INF-α for patients younger than age 65 years and busulfan in the older age group. All three second-line drugs induce phlebotomy-independence in almost all patients with PV and response rates for thrombocytosis or leukocytosis often exceed 80%, which is superior to what was mentioned above for INCB018424. The suggestion that busulfan or pipobroman might be leukemogenic in PV or ET is completely unfounded and is often used as a scare tactic to promote the use of new drugs [16-18, 24-27]. In general, it makes very little sense to me why one would use a non-specific JAK inhibitor, such as INCB018424 [15] or CYT387, [1] for the treatment of ET or PV. The evidence so far suggests that such drugs are inferior to conventional second-line drug therapy for PV or ET in controlling either thrombocytosis or leukocytosis. On the other hand, considering the fact that virtually all patients with PV carry a JAK2 mutation and that such patients may sometimes suffer from drug-refractory pruritus, it is reasonable to investigate the therapeutic value of more selective anti-JAK2 drugs such as TG101348 [28] or SB1518 [29]. Vannucchi et al. [30] presented results from a phase-1/2 study of RAD001, an oral inhibitor of mTOR in PMF and post-PV/ET MF. A total of 30 patients were treated with 10 mg daily, which was considered as the MTD. Non-hematologic toxicity included frequent Grade 2 mouth ulcers and Grade 1/2 hypertriglyceridemia. Grade 3/4 hematological toxicities included anemia in four patients and thrombocytopenia in one patient. According to IWG-MRT criteria, six (23%) patients experienced clinical improvement, which includes >50% spleen size reduction or anemia response. In addition, 11 (52%) of 21 patients had complete resolution of systemic symptoms and 14 (74%) of 19 patients reported disappearance of pruritus. The drug did not affect JAK2V617F allele burden. A set of 46 inflammatory protein markers and cytokines were quantified and some, including IL-10 and MIP-1b, showed significant decrease while others, including Factor VII, IL-8 and MMP-2 showed an increase in post-treatment samples. JAK2V617F activates STAT3/5, RAS/MAPK and PI3/AKT pathways. There is therefore rationale to target the PI3/AKT and mTOR pathways and in vitro studies have demonstrated the therapeutic potential of such a strategy [31, 32]. The above abstract by Vannucchi et al. serves as proof-of-concept in this regard. Gotlib et al. [33] presented results of a Phase-2 study in SM using midostaurin (PKC412), an inhibitor of wild-type and D816V KIT. PKC412 was orally administered to 26 patients at 100 mg BID. SM variants included aggressive SM (ASM; n = 4), SM-CMML (n = 14), SM-MDS (n = 3), SM-MDS/MPN-U (n = 1), and mast cell leukemia (MCL; n = 4). Major response rate per conventional criteria was 38%. What was labeled as MR included normalization of hypoalbuminemia, improvement of hemoglobin and platelet counts, resolution of liver function abnormalities, improvement of pleural effusion and ascites, and reversion of weight loss. Some of these responses were accompanied by improvement in hepatosplenomegaly, a >50% decrease in serum tryptase level and/or marrow mast cell burden, and improvement in mediator symptoms. One patient with MCL had achieved a near complete remission with a decrease of serum tryptase from 763 to <20 ng mL−1, and decrease of marrow MC burden from 60–70% to 5%. The most common drug side effects were nausea, vomiting, diarrhea, and fatigue. Asymptomatic hyperlipasemia occurred in five patients. Treatment had to be discontinued in 18 (69%) patients. PKC412 has activity in SM and might produce substantial reduction in mast cell burden in some patients. However, it is currently not clear which patients with SM stand to benefit from such treatment and more studies are needed to clarify the advantage of PKC412 over treatment with cladribine, which is currently considered first line treatment in ASM or symptomatic indolent SM [34]. Cladribine therapy has been associated with CR/MR/PR rates of 33–58% in ASM, 50–91% in ISM/SSM, and 46% in SM-AHNMD [34]. Cladribine has also been successfully used in MCL [35]. IFN-α is another useful drug for the treatment of SM. In a recent Mayo Clinic study, IFN-α induced a CR/MR/PR rate of 41% and the presence of anemia or elevated ESR was significantly associated with inferior response to IFN-α [36]. Taken together, PKC412 therapy might be most useful in the treatment of ASM or MCL, if combined with either cladribine or IFN-α. I am, however, skeptical about the value of such a strategy in SM-AHNMD. Quintas-Cardama et al. [36] presented a Phase-2 study of subcutaneous Pegasys in 84 patients (median age 51 years) with PV (n = 44) or ET (n = 40). Initial dose was 450 mcg week−1, which was subsequently modified to 90 mcg week−1. After a median follow-up of 40 months, CR rate was 75%. Of five patients with abnormal karyotype at study entry, two reverted to diploid cytogenetics. Overall, 28% of patients had a >50% reduction in JAK2V617F allele burden and 19% had complete molecular response. TET2 or ASXL1 mutational status did not appear to impact the likelihood of achievement of molecular response. Twenty-five (30%) patients were taken off study after a median of 9 months and the reason in half of them was drug toxicity including anorexia, depression, fatigue, ischemic retinopathy, dyspnea, and neuropathy. The results of the current study support the use of pegasys in hydroxyurea-refractory PV or ET. However, controlled studies are needed to assess the value of the drug as first-line therapy. IFN-a can induce molecular remissions in 10–20% of patients but what exactly this means in terms of overall outcome is not clear. Gangat et al. [37] presented a new prognostic model for PMF that incorporates the Dynamic International Prognostic Scoring System (DIPSS) [6] and IPSS-independent prognostic factors including unfavorable karyotype [38], red cell transfusion need [8, 39], and platelets <100 × 109/L [40]. A total of 793 patients from the Mayo clinic constituted the study population and was divided into two groups based on whether or not patients were seen within (n = 428; training set) or beyond (n = 365; test set) their first year of diagnosis. Multivariable analysis that included DIPSS risk category (low, intermediate-1, intermediate-2, and high risk), karyotype (favorable or unfavorable), platelet count or <100 × 109/L) and transfusion status (independent or dependent) was performed using the training set and all four variables were found to be significant as independent predictors of survival (P < 0.0001, <0.0001, 0.0008, and 0.01, respectively). Using the respective hazard ratios (HR) obtained during the multivariable prognostic analysis in the training set, HR-weighted adverse points were assigned: three points for high-risk DIPSS, two points for intermediate-2 risk DIPSS, and one point each for intermediate-1 risk DIPSS, unfavorable karyotype, platelets <100 × 109/L or transfusion need. Accordingly, a refined DIPSS model (i.e., DIPSS-plus) was devised using the training set and subsequently validated in the test set: low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2–3 adverse points) and high-risk (4–6 adverse points). Considering the entire group of 793 study patients, the respective median survivals were 185, 78, 35, and 16 months (P < 0.0001). Finally, multivariable analysis identified platelet count and karyotype as independent predictors of leukemia-free survival. The International Prognostic Scoring System (IPSS) for PMF uses five predictors of inferior survival: age >65 years, hemoglobin <10 g dL−1, leukocytes >25 × 109/L, circulating blasts ≥1% and constitutional symptoms [5]. The dynamic IPSS (DIPSS) utilizes the same prognostic variables but can be applied at any time during the disease course [6]. The current study incorporates IPSS/DIPSS-independent risk factors, namely red cell transfusion need, platelet count <100 × 109/L and unfavorable karyotype, for survival into a new prognostic model (DIPSS-plus) [7]. In other words, DIPSS-plus uses eight instead of five risk factors to define low (no risk factors), intermediate-1 (one risk factor), intermediate-2 (two or three risk factors) and high (four or more risk factors) [7]. Other risk factors that are worthy of further investigation in PMF include nullizygosity for JAK2 46/1 haplotype, [41, 42] low JAK2V617F allele burden [43, 44] and increased plasma levels of IL-8, IL-10, IL-15, or IL-2R [45]. Finally, the above study also identifies unfavorable karyotype and thrombocytopenia as independent risk factors for leukemic transformation. Unfavorable karyotype in PMF includes complex karyotype or sole or two abnormalities that include +8, −7/7q-, i(17q), inv [3], −5/5q-, 12p-, or 11q23 rearrangement [38]. A multiplex biometric [45] sandwich immunoassay was used for simultaneous analysis of 30 cytokine levels in 127 treatment naive patients with PMF. Significant differences were evident for 20 of the 30 cytokines. On univariate analysis, increased levels of 9 of these 20 cytokines were associated with shortened survival: IL-1RA, IL-2R, IL-6, IL-8, IL-12, IL-15, MIP-1a, CXCL10, and MIG. On multivariable analysis, four of these nine cytokines maintained their prognostic value for survival: IL-2R, IL-8, IL-15, and CXCL10. The independent prognostic value of these four cytokines was sustained during additional multivariable analysis that included the Dynamic International Prognostic System Score and cytogenetic risk category. The 127 patients were subsequently stratified into three cytokine risk categories based on the serum levels of IL-2R, IL-8, IL-15, and CXCL10: none elevated, one or two elevated and three or four elevated. The respective median survivals were 69, 37, and 19 months (P = 0.01) and such cytokine risk categorization was both DIPSS and cytogenetic risk independent. Abnormal cytokine expression accompanies the disease process in MF and the levels of proinflammatory cytokines have been shown to be down-regulated by JAK inhibitor therapy [3]. The current study shows that multiple proinflammatory and angiogenic cytokines/chemokines are overexpressed in MF and that the phenomenon has both phenotypic and prognostic consequences. The implications are (i) cytokines/chemokines contribute to disease pathogenesis, (ii) cytokines/chemokines play a role in phenotypic diversity, (iii) certain cytokines/chemokines might serve as potential therapeutic targets, (iv) plasma cytokine levels might be used as additional prognostic parameters, and (v) plasma cytokine/chemokine levels might be used to predict and monitor treatment response and disease progression. Hermine et al. [46] presented results on 44 patients with mastocytosis treated with cladribine. Patients were classified as having cutaneous mastocytosis (CM; n = 3) indolent SM (ISM; n = 19), smoldering SM (SSM; n = 3), aggressive SM (ASM; n = 12) or SM with an associated clonal hematologic non-MC-lineage (SM-AHNMD; n = 6), mast cell leukemia (MCL; n = 1). All patients had failed previous symptomatic therapy and/or interferon-α (n = 10) or kinase inhibitors (n = 7). Cladribine was given at 0.15mg/kg/day in a 2-hr infusion or subcutaneously for 5 days, repeated every 1–2 months, for a median of four cycles. After a median follow up of 35 months, no opportunistic infections were seen with the exception of zoster infections in two patients. Responses occurred in 24/31 patients with urticaria pigmentosa, 17/35 with fatigue, 14/24 with flushing, 9/24 with pruritus, 9/21 with abdominal pain, 1/9 with ascites, 11/23 with diarrhea, 8/16 with weight loss, 4/14 with headache, 5/10 with cough (5/10), 7/20 with splenomegaly, 2/6 with lymphadenopathy, 0/2 with pleural effusions and 5/19 with neuropsychological symptoms. In addition, eosinophil count normalized in 7/10 cases and a substantial decrease in tryptase levels was also noted. Overall, major (MR) and partial (PR) responses were observed in 7/12 patients with ASM, 3/3 SSM, 17/19 ISM, 2/3 CM but in none of the patients with SM-AHNMD. Median duration of response was ∼20 months. The current study validates the value of cladribine in SM [47] and provides clinically useful information on where the drug works best in terms of SM variant and specific symptom. However, the results look different than those recently published from the Mayo Clinic [34]. The current French study suggests that cladribine might not be effective in SM-AHNMD whereas the MR/PR response rate in this SM variant was reported at 46% in the Mayo Clinic study. Similarly, the MR/PR rates for ASM (58%) and SSM/ISM (91%) were substantially higher than those reported by the Mayo investigators for both ASM (33%) and ISM (50%). I suspect that the discrepancy in response rates is secondary to different interpretation of current conventional criteria for response measurement in SM, which are loose and vague. Regardless, in the Mayo Clinic study, [34] presence of leukocytosis, monocytosis or circulating immature myeloid cells was significantly associated with inferior response to cladribine. This year, my top three clinically-oriented ASH abstracts were (i) the study by Pardanani et al. [1] showing for the first time that a JAK inhibitor can induce a substantial response rate in MF-associated anemia, (ii) the study by Barbui et al. [9] showing for the first time the clinical relevance of distinguishing ET from prefibrotic PMF and in the process affirming the truly indolent clinical course of ET, and (iii) the study by Vaidya et al. [45] showing the prognostic relevance of plasma cytokines in PMF. All three studies carry a major impact on clinical practice and there is little doubt that we will be hearing more about them in the coming months.