Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes

BACKGROUND:

In the AZA‐001 trial, azacitidine (75 mg/m²/d subcutaneously for Days 1‐7 of every 28‐day cycle) demonstrated improved survival compared with conventional care regimens in patients with International Prognostic Scoring System‐defined intermediate‐2‐ or high‐risk myelodysplastic syndrome and World Health Organization‐defined acute myeloid leukemia with 20% to 30% bone marrow blasts.

METHODS:

This secondary analysis of the AZA‐001 phase 3 study evaluated the time to first response and the potential benefit of continued azacitidine treatment beyond first response in responders.

RESULTS:

Overall, 91 of 179 patients achieved a response to azacitidine; responding patients received a median of 14 treatment cycles (range, 2‐30). Median time to first response was 2 cycles (range, 1‐16). Although 91% of first responses occurred by 6 cycles, continued azacitidine improved response category in 48% of patients. Best response was achieved by 92% of responders by 12 cycles. Median time from first response to best response was 3.5 cycles (95% confidence interval [CI], 3.0‐6.0) in 30 patients who ultimately achieved a complete response, and 3.0 cycles (95% CI, 1.0‐3.0) in 21 patients who achieved a partial response.

CONCLUSIONS:

Continued azacitidine therapy in responders was associated with a quantitative increase in response to a higher response category in 48% of patients, and therefore may enhance clinical benefit in patients with higher‐risk MDS. Cancer 2011. © 2011 American Cancer Society.     

A call for action: Increasing enrollment of untreated patients with higher‐risk myelodysplastic syndromes in first‐line clinical trials

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher‐risk myelodysplastic syndromes (HR‐MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real‐life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24‐month median survival observed with azacitidine in the landmark AZA‐001 trial has not been replicated in population‐based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR‐MDS is significantly lower than what was observed in the AZA‐001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front‐line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR‐MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider‐scale enrollment in front‐line HR‐MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662–3672. © 2017 American Cancer Society     

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

Patients with lower‐risk myelodysplastic syndromes (LR‐MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter‐individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS‐relevant genes in 159 patients with LR‐MDS using next‐generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129‐4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144‐8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662‐14.230) and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848‐16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273‐4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR‐MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher‐risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of the IPSS with mutation status/burden of certain MDS‐relevant genes may improve the prognostication of patients with LR‐MDS and could help identify those with worse‐than‐expected prognosis for more aggressive treatment.     

Five‐day regimen of azacitidine for lower‐risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single‐arm phase 2 trial

Although azacitidine is the first‐line drug for higher‐risk myelodysplastic syndrome (MDS) patients, its efficacy for lower‐risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5‐day regimen of azacitidine (AZA‐5) for lower‐risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower‐risk MDS based on the French‐American‐British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51‐88). These patients received AZA‐5 (75 mg/m²; once daily for 5 sequential days). The median number of AZA‐5 courses was 8 (range: 1‐57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA‐5 is feasible and effective for lower‐risk MDS patients as well as for higher‐risk MDS patients.     

A single‐arm,multicenter, open‐label phase 2 study of lapatinib as the second‐line treatment of patients with locally advanced or metastatic transitional cell carcinoma

BACKGROUND:

The treatment of recurrent transitional cell carcinoma (TCC) remains an unmet clinical need. This study assessed lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER‐2, as second‐line therapy in patients with locally advanced or metastatic TCC.

METHODS:

This was a single‐arm, multicenter, open‐label, prospective phase 2 study. Patients with TCC whose disease progressed on prior platinum‐based chemotherapy received lapatinib until disease progression or unacceptable toxicity, with evaluations for response by Response Evaluation Criteria In Solid Tumors criteria performed every 8 weeks. The primary endpoint of the current study was objective tumor response rate. Secondary endpoints included safety, time to disease progression, and overall survival.

RESULTS:

Fifty‐nine patients were enrolled in the study, 25 of whom (42%) could not be evaluated for response. The primary endpoint of an objective response rate (ORR) >10% was observed in 1.7% (95% confidence interval [95% CI], 0.0%‐9.1%) of patients; however, 18 (31%; 95% CI, 19%‐44%) patients achieved stable disease (SD). The median time to disease progression and overall survival (OS) were 8.6 weeks (95% CI, 8.0 weeks‐11.3 weeks) and 17.9 weeks (95% CI, 13.1 weeks‐30.3 weeks), respectively. Clinical benefit (ORR and SD) was found to be correlated with EGFR overexpression (P = .029), and, to some extent, HER‐2 overexpression. The median OS was significantly prolonged in patients with tumors that overexpressed EGFR and/or HER‐2 (P = .0001). Lapatinib was well tolerated.

CONCLUSIONS:

The study was considered to be negative because it did not meet its primary endpoint; however, further analysis demonstrated an improvement in OS in a subset of patients with tumors overexpressing EGFR and/or HER‐2, which is encouraging and warrants further investigation. Cancer 2009. © 2009 American Cancer Society.     

A phase II open‐label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome

Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m² via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55–84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate‐1, five intermediate‐2 and two high‐risk. Median chemotherapy courses were one (1–3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction – from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non‐haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35–72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS.     

Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population‐based study

Benzene exposure is one of the few well‐established risk factors for myeloid malignancy. Exposure to other chemicals has been inconsistently associated with hematologic malignancies. We evaluated occupational and residential chemical exposures as risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using population‐based data. AML and MDS cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota driver's license/identification card list. Chemical exposures were measured by self‐report. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). We included 265 MDS cases, 420 AML cases and 1388 controls. We observed significant associations between both MDS and AML and benzene (OR = 1.77, 95% CI 1.19, 2.63 and OR = 2.10, 95% CI 1.35, 3.28, respectively) and vinyl chlorides (OR = 2.05, 95% CI 1.15, 3.63 and OR = 2.81, 95% CI 1.14, 6.92). Exposure to soot, creosote, inks, dyes and tanning solutions and coal dust were associated with AML (range ORs = 2.68–4.03), while no association was seen between these exposures and MDS (range ORs = 0.57–1.68). Pesticides and agricultural chemicals were not significantly associated with AML or MDS. Similar results were observed in analyses stratified by sex. In addition to providing risk estimates for benzene from a population‐based sample, we also identified a number of other occupational and residential chemicals that were significantly associated with AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases.     

Phase 1/2 study evaluating the safety and efficacy of DSP‐7888 dosing emulsion in myelodysplastic syndromes

DSP‐7888 is an immunotherapeutic cancer vaccine derived from the Wilms’ tumor gene 1 (WT1) protein. This phase 1/2 open‐label study evaluated the safety and efficacy of DSP‐7888 dosing emulsion in patients with myelodysplastic syndromes (MDS). DSP‐7888 was administered intradermally (3.5 or 10.5 mg) every 2 weeks for 6 months and then every 2‐4 weeks until lack of benefit. Twelve patients were treated in phase 1 (3.5 mg, n = 6; 10.5 mg, n = 6), with no dose‐limiting toxicities reported. Thus, the 10.5 mg dose was selected as the recommended phase 2 dose, and 35 patients were treated in phase 2. Forty‐seven patients received ≥1 dose of the study drug and comprised the safety analysis set. The most common adverse drug reaction (ADR) was injection site reactions (ISR; 91.5%). Grade 3 ISR were common (58.8%) in phase 1 but occurred less frequently in 2 (22.9%) following implementation of risk minimization strategies. Other common ADR were pyrexia (10.6%) and febrile neutropenia (8.5%). In the efficacy analysis set, comprising patients with higher‐risk MDS after azacitidine failure in phases 1 and 2 (n = 42), the disease control rate was 19.0%, and the median overall survival (OS) was 8.6 (90% confidence interval [CI], 6.8‐10.3) months. Median OS was 10.0 (90% CI, 7.6‐11.4) months in patients with a WT1‐specific immune response (IR; n = 33) versus 4.1 (90% CI, 2.3‐8.1) months in those without a WT1‐specific IR (n = 9; P = .0034). The acceptable safety and clinical activity findings observed support the continued development of DSP‐7888 dosing emulsion.     

Efficacy and safety of ruxolitinib in intermediate‐1 IPSS risk myelofibrosis patients: Results from an independent study

Patients with myelofibrosis at intermediate‐1 risk according to the International Prognostic Score System are projected to a relatively long survival; nonetheless, they may carry significant splenomegaly and/or systemic constitutional symptoms that hamper quality of life and require treatment. Since registrative COMFORT studies included only patients at intermediate‐2/high International Prognostic Score System risk, safety and efficacy data in intermediate‐1 patients are limited. We report on 70 intermediate‐1 patients treated with ruxolitinib according to standard clinical practice that were evaluated for response using the 2013 IWG‐MRT criteria. At 6 months, rates of spleen and symptoms response were 54.7% and 80% in 64 and 65 evaluable patients, respectively. At 3 months, ruxolitinib‐induced grade 3 anemia and thrombocytopenia occurred in 40.6% and 2.9% of evaluable patients, respectively. Notably, 11 (15.9%) patients experienced at least one infectious event ≥grade 2. Most (82.6%) patients were still on therapy after a median follow‐up of 27 months. These data support the need for standardized guidelines that may guide the decision to initiate ruxolitinib therapy in this risk category, balancing benefit expectations and potential adverse effects.     

Phase I,multicenter, open‐label,dose‐escalation study of sonidegib in Asian patients with advanced solid tumors

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose‐limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open‐label, single‐arm, multicenter, two‐group, parallel, dose‐escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov : NCT01208831.)