Tefferi, Ayalew

SummaryMyelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK‐STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro‐inflammatory cytokines (IL‐1 ß, TGF‐ß), growth factors (b‐FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation‐enhanced (MIPSS 70‐plus version 2.0) and genetically‐inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for risk‐adapted therapeutic decisions. A major challenge remains the dearth of disease‐modifying drugs, whereas allogeneic transplant offers the chance of long‐term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.

7059 Background: Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ~6-7 mos median OS in relapsed/refractory (r/r) setting. Splenomegaly is a poor prognostic factor and potential target in CMML. CD123 is detected on blasts, monocytes, and neoplastic microenvironmental plasmacytoid dendritic cell (pDC) infiltrates part of the CMML malignant clone (Solary, et al). Tagraxofusp, a novel CD123 targeted therapy, demonstrated high levels of activity in BPDCN, an aggressive hematologic malignancy derived from CD123-expressing pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel approach in CMML. Methods: Multicenter, 2-stage Ph1/2 enrolling patients (pts) with r/r CMML. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed on days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing), pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 20 pts (12 CMML-1; 8 CMML-2) enrolled. 18 pts 2nd-line (2 pts in 1L), HMAs most common prior therapy. Median age 69 (43-80); 81% male. 11 (52%) had baseline splenomegaly (spleen palpable below left costal margin by physical exam) of 2-27 cm. Most common TRAEs: hypoalbuminaemia (35%), thrombocytopenia (35%), nausea (30%), vomiting (30%), and fatigue (20%). Most common ≥Gr3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome in 3 pts (15%; all Gr1&2). 100% (10/10) of pts with splenomegaly had spleen response: 80% (8/10) had reductions ≥50% and 67% (4/6) with spleen size ≥5 cm had reductions ≥50%. 3 pts achieved bone marrow complete responses, including 1 pt bridged to SCT in remission. Conclusions: Tagraxofusp demonstrated single agent activity in CMML as 80% of pts showed ≥50% reduction in splenomegaly by palpation. Splenomegaly in CMML, as in myelofibrosis, is a major cause of morbidity and associated with poor prognosis and impaired QoL. Targeting splenomegaly in myeloid neoplasms with proliferative features may be an important therapeutic goal. Given CD123 expression on CMML blasts, monocytes, and malignant pDCs, tagraxofusp may offer a targeted approach, especially in pts with splenomegaly. Updated safety and efficacy data to be presented. Registrational trial planned. Clinical trial information: NCT02268253.

7058 Background: Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. CD123 is expressed on a variety of malignancies, including MF. CD123+ plasmacytoid dendritic cells (pDCs), in the MPN microenvironment, including chronic myelomonocytic leukemia and MF, may be tumor-promoting. Monocytosis in MF associated with rapid disease progression and short survival, suggesting an accelerated disease phase. Notably, monocytes share a common precursor with CD123+ pDCs. Tagraxofusp, a novel CD123 targeted therapy, demonstrated high activity in patients with BPDCN, an aggressive hematologic malignancy derived from CD123+ pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel therapeutic approach in MF. Methods: Multicenter, 2-stage Ph 1/2 trial enrolling patients (pts) with MF relapsed, refractory, or intolerant to JAKi. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed daily days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing): pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 23 r/r pts treated. Median age 69 (55-81); 57% female. DIPSS Plus: 4% INT-1, 55% INT-2, 41% high. Baseline platelets: median 59 K/uL (15-579); 70% (16/23) <100 K/uL, 8 pts <50 K/uL. 87% (20/23) baseline splenomegaly (palpable ≥5 cm below left costal margin by physical exam). Most common TRAEs: headache (22%), hypoalbuminaemia (22%), ALT incr. (17%) and thrombocytopenia (17%). Most common ≥Gr3 TRAE thrombocytopenia (2%). Capillary leak syndrome in 1 pt (4%; Gr3). 57% (8/14) of pts with baseline spleen ≥5cm BCM spleen responses: 43% (6/14) had ≥29% and 21% (3/14) had ≥45% reduction. 100% of pts with baseline spleen ≥5cm and monocytosis splenomegaly reductions: 80% (4/5) had ≥29% and 40% (2/5) had ≥45%. 6 pts (3 monocytosis pts and 5 pts platelets <100 K/uL) had 6 mos+ duration, 9 pts ongoing. Conclusions: Tagraxofusp demonstrated single agent activity (reduction in splenomegaly) and manageable safety in R/R MF, including pts with monocytosis, an unmet medical need. Given the presence of CD123+ pDCs, tagraxofusp may offer a novel targeted approach in MF. Updated data to be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.

7053 Background: The revised International Prognostic Scoring System (IPSS-R) aids in prognosticating MDS. The percentage (%) of blasts in the bone marrow is one of the major determinants of the scoring system. The aspirate blast % is utilized as the standard of care, but there could be discrepancies in the blast % reported by the aspirate and the biopsy. We aim to study the possible use of bone marrow biopsy blasts in MDS-EB in calculating IPSS-R. Methods: The MDS database was reviewed for cases of MDS-EB after due IRB approval. We calculated IPSS-R scores based on the aspirate blast % (IPSS-RAsp) and biopsy blast % (IPSS-RBx). The biopsy blast % was reported morphologically or by the CD34 stain. Whenever a range was reported the highest value was utilized as the blast %. Suboptimal aspirates were excluded from the study. The overall survival (OS) was determined by IPSS-RAsp, IPSS-RBx and IPSS-R highest blast (IPSS-RHi). OS estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Uno’s concordance statistic was used to compare all 3 risk scoring systems. Results: Of 1322 patients, 431 (33%) cases were identified with MDS-EB; out of which 173 cases had both blasts reported in the biopsy and the aspirate. Out of 173 cases, 35 (20%) had MDS-EB1, and 61 (35%) had MDS EB-2 based on both biopsy and aspirate (concordant cases). Seventy seven (45%) patients changed from EB-1 to EB2 or vice versa based on the biopsy blast (44/77 (57%) cases were upstaged). The OS outcomes based on the IPSS-RBx biopsy showed a clear and meaningful separation with median OS decreasing with increased risk but IPSS-RAsp and IPSS-RHi did not (Table). We compared the 3 models for observed OS differences using the Uno model and there was no statistically significant difference. Conclusions: IPSS-RBx (but not IPSS-RAsp and IPSS-RHi) identified prognostic groups for OS with median OS decreasing with increased risk. The small sample size may have led to an insignificant effect on model power by Uno model. This finding needs to be validated by other centers. [Table: see text]

7109 Background: We previously reported results of treating MF patients with 3 cycles of 300, 400, or 500 mg of SAR302503 (NCT01420770; Blood 2012;120:21 Abs 2837). This is a report of efficacy and safety after 6 cycles. Methods: Patients ≥18 years of age with intermediate-2 or high-risk MF and splenomegaly were eligible. SAR302503 is administered orally, once a day in consecutive 4-week cycles until disease progression or unacceptable toxicity. Spleen response (≥35% reduction in spleen volume vs baseline) was assessed by MRI/CT (blinded independent central review). Results: 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status was balanced in all but the 300 mg group (70% high-risk). Most patients were JAK2V617F positive (90%) and blood transfusion independent (81%). Spleen response rates at the end of cycle (EOC) 6 (secondary end point) were 30% (3/10) in the 300 mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg compared with EOC 3 rates of 30%, 50%, and 64%, respectively. One patient on 500 mg who had a spleen response at EOC 3 (39% reduction), but not at EOC 6 (25% reduction) had dose reductions to 200 mg due to anemia. Median number of cycles was 13 (range, 2–17) and 24 patients have been on treatment >12 months. SAR302503 reduced baseline constitutional symptoms at the EOC 3, with the greatest responses for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety and abdominal pain, each in 10/18 (56%). Most common adverse events were anemia and diarrhea, with grade 3–4 rates of 58% and 13%, respectively. The rate of grade 3–4 thrombocytopenia was 16%. There was no grade 3–4 neutropenia. The diarrhea rate tended to decrease after the first 2 treatment cycles. There have been no reports of withdrawal syndrome after stopping SAR302503. Median JAK2V617F allele burden was 93% at baseline, 87% at the EOC 3, and 78% at EOC 6 in 19/26 patients who had available samples. The expression of 22 of 97 cytokines was significantly regulated (≥1.5 fold difference; p<0.05) after cycle 1. Conclusions: In this Phase II trial, continued treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly. Symptom data will be updated. Clinical trial information: NCT01420770.

TPS6641 Background: Hydroxyurea is widely used to treat patients with high-risk PV and ET. However, some patients are either clinically resistant to hydroxyurea or have unacceptable side effects, supporting the need for active therapeutic options in this setting. SAR302503 is an orally administered selective JAK-2 inhibitor that reduced symptom burden and provided a durable clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in a Phase 1/2 trial of patients with primary myelofibrosis (MF), post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789; Pardanani, ASH 2011; Abs 3838). Based on the results in MF, in October 2011 we initiated a Phase 2 trial to evaluate SAR302503 for the treatment of patients with PV and ET who are resistant or intolerant to hydroxyurea (NCT01420783; ARD12042). Methods: Eligibility criteria include age of at least 18 years, ECOG PS 0–2, and hydroxyurea resistant PV or ET as defined by European LeukemiaNet Consensus Criteria (Blood 2009;113:4829). Patients are being randomized (1:1:1) to receive 100, 200, or 400 mg of SAR302503 orally once daily in consecutive 28-day cycles for at least 8 cycles in the absence of progression or unacceptable toxicity. The primary end points will be assessed after the completion of 8 cycles and are: for PV, the proportion of patients maintaining a hematocrit below 45% without phlebotomy for at least 3 months; for ET, the proportion of patients with a platelet count lower than 400 × 109/L for at least 3 months. Secondary objectives include safety, response rate, pharmacokinetics, pharmacodynamics as measured by JAK2V617F allele burden and STAT3 phosphorylation inhibition, assessment of disease-related symptoms, and quality of life. Enrollment of the planned total of 90 patients is ongoing at approximately 45 sites globally. Twelve patients have been enrolled as of January 2012.

TPS6639 Background: SAR302503 is an orally administered selective JAK-2 inhibitor being evaluated for the treatment of MF. In a phase 1 study, SAR302503 reduced spleen size and disease-related symptoms and provided clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing open-label extension of this trial confirmed the durability of those results and found that doses between 400–500 mg/day of SAR302503 represented the optimal balance between safety and efficacy (Pardanani, ASH 2011;Abs 3838). These results led us to initiate a Phase 3 trial in December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 mg/day, compared with placebo, for the treatment of patients with MF (NCT01437787; EFC12153). Methods: Eligibility criteria include age of at least 18 years, platelets >50,000/µl, ECOG PS 0–2, and a diagnosis of high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF according to IPSS criteria (Blood 2009;113:2895). Patients are being randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned treatment will continue as long as patients are deriving benefit or until progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or in case of progression before completion of 6 cycles according to predefined criteria. The primary endpoint is spleen response (≥35% reduction in spleen volume by MRI/CT at the end of cycle 6). Key secondary objectives are symptom response rate and durability of spleen response. Additional secondary endpoints include assessment of allele burden and bone marrow fibrosis reduction. It is planned to randomize 75 patients per treatment group at approximately 130 sites worldwide.

6614 Background: CDKN2A locus on chromosome 9p21 is implicated in altered molecular pathways leading to leukemogenesis as a tumor suppressor by inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle division during G1/S phase. Deletion of CDKN2A locus is frequently seen in ALL, although prognostic significance remains unclear. Methods: Retrospective chart review at Mayo Clinic between 8/2005-11/2011 was performed on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization (FISH) studies at diagnosis. Survival estimate was calculated using Kaplan-Meier statistics. Event-free survival (EFS) was defined as time between diagnosis and induction failure, relapse, or death, while overall survival (OS) as time between diagnosis and death Results: Out of 27 pts who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions (8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics (none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on FISH). There was no significant difference in median age, gender, WBC, hemoglobin, platelet count, LDH or complete remission (CR) rate (p=0.924) between the two groups. CDKN2A-deleted pts had higher circulating blasts (34% vs 16%, p=0.017). Of 13 CDKN2A-deleted pts, chromosome 9p was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2A-deleted group, allogeneic stem cell transplant (ASCT) was performed in 7 (47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2A-deleted pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2A-deleted pts compared to normal FISH group (22% vs 60%, p=0.042), while 5-year OS was 72% vs 60% (p=0.308), respectively. Excluding the 4 bcr/abl fusion pts, 5-year EFS was still statistically significant (p=0.008). In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p=0.006) and OS (100% vs 42%, p=0.016) were significantly superior in pts who received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in pts with B-ALL. Majority of 9p abnormalities were only found by FISH testing and missed by conventional cytogenetics. In CDKN2A deleted pts, ASCT gave overall survival advantage. Further investigation through larger cohorts of pts is needed to validate these findings.

7110 Background: Abnormal cytokine expression may represent an inflammatory response that contributes to the clinical phenotype of MF. Some constitutional symptoms (eg. fever, fatigue, pruritus, cachexia) are thought to be caused by elevated cytokines. In phase I/II studies, SAR302503 reduced splenomegaly and constitutional symptoms in patients with MF. Here, we report the effects of SAR302503 on the expression of 97 cytokines in MF patients enrolled in a Phase II study (NCT01420770) and the relationship to clinical response (spleen size), pharmacokinetic (PK) exposure, and body weight changes. Methods: Thirty-one patients were randomized to receive 300, 400, or 500 mg of SAR302503 orally, once daily, continuously in 4-week cycles. Plasma cytokines were measured at baseline and at the end of 4, 8, and 12 weeks of treatment using a microsphere-based immuno-multiplex assay (Rules Based Medicine). Results: Complete sample sets were available for 29/31 patients. A total of 28 cytokines predominantly involved in immune/inflammation pathways were regulated ≥1.5-fold (ANOVA P<0.05) and of these, 19 were regulated at all time points, indicating rapid and sustained modulation by JAK2 inhibition. At 4 weeks, 16 cytokines were down-regulated, including TNFα, IL-1RA, and IL-18, and 6 were up-regulated, including leptin, EPO, and adiponectin. Hierarchical clustering of the 22 regulated cytokines enriched patients into spleen responder (≥35% reduction in spleen volume by MRI) and non-responder groups, suggesting a link between cytokine modulation and clinical response. Moderate correlations (P<0.05) with spleen volume reduction at the end of week 12 were seen for a subset of regulated cytokines, including adiponectin and TNFα. Levels of the majority of the regulated cytokines tended to correlate with steady state PK exposure at week 4. A positive association with weight changes at week 24 were observed for leptin and adiponectin at week 4 (P<0.05). Conclusions: This analysis shows that SAR302503 treatment modulated the expression of circulating cytokines in MF patients in association with changes in clinical activity, PK exposure, and symptom improvement (weight gain). Clinical trial information: NCT01420770.

7077 Background: MDS includes a heterogenous group of hematopoietic stem cell malignancies characterized by ineffective hematopoiesis and recurring clonal cytogenetic abnormalities with poorly understood functional consequences. Interstitial deletion of chromosome 5 including band q31 is of special interest currently because of the striking effectiveness of lenalidomide therapy in patients with this lesion. Methods: We reviewed the clinical and pathological features of 175 consecutive patients with 5q31 deletions whose final diagnosis was MDS from 1996 to 2006. Patients not meeting the definition of a clonal chromosomal anomaly (i.e., only 1 abnormal metaphase) and those with >20% marrow blasts (now defined as AML) were excluded. Results: The median age at diagnosis was 73 years old (range 8–91). The 5 most common MDS subtypes (WHO classification) were RAEB2 (38 cases), 5q- syndrome (33 cases), MDS NOS (26 cases), RCMD (22 cases), and RAEB1 (20 cases). Chromosomal breakpoints encountered most frequently were q13q33 (86 cases), q15q33 (38 cases), and q22q33 (14 cases). The 5q deletion was present as a sole cytogenetic anomaly in 31%, was present along with one other anomaly in 10%, and was part of complex karyotype in 59%. Median time to death from confirmation of diagnosis at our institution was only 7.2 months (range 1 month –1.8 years). Survival was greatest in those diagnosed with 5q- syndrome, but the median survival time of 1.8 years (p=0.001) was lower than reported in other series. Survival was also superior in women (7.9 months, versus 6.6 months for men, p=0.05) and those with non-complex cytogenetics (1.44 versus 0.41 years, p<0.001). Poorer survival was noted in those with prior chemotherapy (median 6.6 months versus 7.6 months, p=0.01). Differences in breakpoint (p=0.55) and number of metaphases involved with the 5q abnormality (p=0.08) did not have a statistically significant impact on survival. Conclusion: Classic 5q- syndrome as defined by the WHO represents only a minority of MDS patients with interstitial 5q deletions. Although the short survival in our series compared with previous reports may be due in part to referral bias, it is also possible that deletions of chromosome 5q are less benign than previously suspected. No significant financial relationships to disclose.