Annual congress highlights benefits of tailoring treatment to disease risk factors, patients’ status

The European Haematology Association’s annual congress took place in June in London. A number of themes emerged from this large and interesting meeting, which spotlighted several exciting and meaningful therapeutic advances.

In his pre-congress briefing, Bob Lowenberg, MD, developed the notion that patients with acute myeloid leukemia may have been receiving excessive doses of cytarabine in the globally accepted combination with an anthracycline.

Referring to a recently published paper in The New England Journal of Medicine from Dutch (HOVON) and Swiss (SAKK) groups, Lowenberg emphasized the usually recommended doses of cytarabine, 2,000 mg/m² to 3,000 mg/m² twice daily in cycle 2 did not confer any benefit when compared with 1,000 mg/m² in the intermediate arm of the randomized trial. The trial enrolled patients aged 60 years or younger. Older patients were excluded based on predicted toxicity in the high-dose groups. Patients who received the lower intermediate dose had shorter hospital stays and fewer blood transfusions.

Importance of targeted therapy

Lowenberg developed the theme of tailoring treatment to both disease risk factors and patients’ status in his review of genetic markers in relation to the therapeutic management of AML. An example of this approach was provided by a joint US/European phase 2 trial of AC220 monotherapy in patients with relapsed/refractory AML with FLT3-ITD mutation — a very poor prognostic group.

Quizartinib (AC220) is a potent narrow spectrum inhibitor of FLT3 tyrosine kinase with activity in FLT3-ITD-positive patients. Composite complete remission for patients aged older than 60 years refractory to first-line therapy was 36%. Composite complete remission for the cohort of younger patients refractory to second-line therapy or stem cell transplant was 48%.

Toxicity was substantial but dose reductions seemed to ameliorate the problems without affecting efficacy. This example continues the hope that targeted therapy will develop and improve, and that a more flexible approach to therapeutic trials of the many potential agents may accelerate their introduction into clinical practice as suggested by Robert Hills, MA, MSc, DPhil, and Alan Burnett, MD, FRCP, in their “pick a winner” approach to trialling new drugs.

In another example of careful comparison of the impact new agents combined with conventional therapies in multiple myeloma have in younger patients, Antonio Palumbo, MD, and colleagues from Italy explored whether the use of lenalidomide with chemotherapy alone could replace the need for high-dose melphalan and autologous stem cell rescue. The results showed clear benefit for the transplant arm in terms of PFS and complete remissions, though effects on OS could not be assessed.

Hanneke Kluin-Nelemans, MD, presented results of research conducted along with the European Mantle Cell Lymphoma (MCL) Network. Results showed that elderly patients who received MCL maintenance therapy with rituximab every 2 months — particularly patients who had responded to R-CHOP in induction — had substantially improved PFS and complete remission, so much so that they recommend maintenance for all elderly patients with MCL. This was a welcome report, because older patients comprise the majority of lymphoma and leukemia sufferers.

Edward Gordon-Smith

One disease that does not affect the elderly especially is hairy cell leukemia (HCL). The pathogenesis of HCL is obscure. A group from Italy, along with colleagues from the United States and Germany, reported finding mutations in the BRAF gene, BRAF V600E, in all patients with HCL but not in other lymphomas, though the mutation is oncogenic in a number of other tumors. In vitro inhibition of active BRAF in HCL cells from five patients led to a marked decrease in phosphorylated products of the BRAF-activated pathway, suggesting there may be scope for targeted therapy in this disease.

COMFORT-I and II

The Myeloproliferative Neoplasms (MPN) section of this year’s European Haematology Association meeting was dominated by presentations of novel therapies for myelofibrosis (MF). Approximately half the patients with MF have a gain of function mutation in the JAK2 gene associated with dysregulation of the JAK signaling pathway, but dysregulation occurs in all patients.

Results of two phase 3 trials (COMFORT-I and COMFORT-II) of the JAK inhibitor most advanced in development, INC424 — now to be known as ruxolitinib — were presented. Primary endpoints included spleen volume reduction and changes in symptom scoring. These become more relevant when the three main features of MF are considered — massive splenomegaly, significant and sometimes disabling constitutional symptoms, and anemia. A 35% reduction in spleen volume was chosen, as this previously has been demonstrated to equate to a 50% reduction in palpable spleen length.

In the COMFORT-I study, presented by Srdan Verstovsek, MD, of The University of Texas MD Anderson Cancer Center, ruxolitinib was compared with placebo. The COMFORT-II trial, presented by Claire Harrison, MD, of Guy’s and St Thomas’ hospitals in London, compared ruxolitinib with the best-available therapy.

In both trials, ruxolitinib was significantly superior to either placebo (COMFORT-I) or best-available therapy (COMFORT-II) with regard to spleen size reduction, symptom burden and quality of life (QOL). The benefit of ruxolitinib was observed regardless of JAK mutational status.

The randomized, double blind, placebo-controlled COMFORT-I trial enrolled 309 patients with intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF). They were randomly assigned to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). Ruxolitinib was dosed at 15 mg or 20 mg, depending on the baseline platelet count. Patients in the placebo arm could crossover to the ruxolitinib arm upon disease progression, and nearly a quarter of patients did crossover (11% prior to week 24 and 13% after week 24).

After a median follow-up of 32 weeks, a significantly higher proportion of patients on the ruxolitinib arm attained the primary endpoint of at least a 35% reduction in spleen volume after 24 weeks of therapy (41.9% vs. 0.7% with placebo; P<.0001). Ruxolitinib also was more effective than placebo regarding the proportion of patients with at least a 50% improvement in symptom burden (45.9% vs. 5.3%; P<.0001).

Symptoms that improved with ruxolitinib included abdominal discomfort, pain under the left ribs, early satiety, night sweats, itching, bone or muscle pain, and inactivity. For each parameter, comparisons between ruxolitinib and placebo were highly significant (

P<0.01). Ruxolitinib was generally well tolerated. The two grade-3/grade-4 adverse events observed more frequently with ruxolitinib compared with placebo were thrombocytopenia (12.9% vs. 1.3%) and anemia (45.2% vs. 19.2%). Both were manageable with dose adjustments. Only one patient in each arm discontinued treatment because of toxicity.

The open-label COMFORT-II trial enrolled 219 patients with intermediate-2 or high risk PMF, PPV-MF or PET-MF. They were randomly assigned to oral twice-daily ruxolitinib administered at 15 mg or 20 mg (146 patients) or to best-available therapy (73 patients). Patients received the assigned treatment for 48 weeks, although 25% of patients in the control arm crossed over to ruxolitinib due to disease progression.

In the best-available therapy arm, 67% of patients received at least one medication, while the remaining 33% received no medication. The most commonly administered agents were hydroxyurea (47% of patients) and glucocorticoids (16% of patients). Mean spleen volumes were 12-fold greater than normal at baseline.

Ruxolitinib achieved at least a 35% reduction in spleen volume at week 48 in 28.5% of patients, compared with 0% for best-available therapy (P<.0001). The median time to response was 12 weeks, the first point at which responses were assessed. This highly significant improvement in spleen volume was accompanied by marked improvement in QOL measures. In contrast, patients who received best-available therapy experienced either no change or worsening of symptoms during the study.

As in COMFORT-I, ruxolitinib was associated with myelosuppression. Grade-3/grade-4 thrombocytopenia was observed in 8% of patients who received ruxolitinib and in 7% of patients who received best-available therapy. Grade-3/grade-4 anemia was reported in 42% of patients who received ruxolitinib and 31% of patients who received best-available therapy. Nearly two-thirds of patients had grade-1/grade-2 anemia at baseline. Although a higher proportion of ruxolitinib-treated patients required red blood cell transfusions during the study (51% vs. 38%), the mean volume transfused per month was similar between arms (0.86 U/month for ruxolitinib-treated patients and .91 U/month for those who received best-available therapy).

Neither study reported a significant survival benefit, although the follow-up period was too short to evaluate effects on survival. Moreover, crossovers from the control arms will further complicate the analysis.

Response to therapy

Disappointingly, an abstract from Jean-Jacques Kiladjian, MD, and colleagues demonstrated that while Pegasys has efficacy in reducing JAK2 mutant allele burden, TET-2–positive clones are not affected by this therapy.

U.K. and Nordic collaborators reported a phase 2 trial of vorinostat therapy in ET and PV with the agent demonstrating some meaningful responses for those patients who were able to tolerate it.

Pomalidomide data also were presented from Germany. Data from a two-stage protocol showed some responses for anemic patients (some of whom achieved transfusion independence) and thrombocytopenic patients with this agent. Interestingly, most responses were seen after the third month with the addition of prednisolone.

Finally, an interesting abstract from Madrid focused upon use of European LeukemiaNet response criteria to assess patients with PV (n=38) and ET (n=108). In this patient population, followed for a maximum of 20 years, only those who demonstrated a lack of response to therapy developed myeloid transformation, suggesting this is an important population of patients for newer therapies.

Measurement of symptoms also was a significant focus of this meeting, with data presented from many EU countries utilizing the increasingly refined MPN-SAF, validating its use in different languages and correlating results with EORTC QLQ-C30. Symptom abatement is a feature of novel therapies such as JAK inhibitors, thus robust and appropriate assessment is becoming more important in this field.

Significance of mutations

Data with regard to mutations and their importance in clinical manifestations also was presented in four abstracts from this meeting. Alessandro Vannucchi, MD, and colleagues reported that EZH2 mutations are associated with poor survival independent of IPSS score or JAK2V617F status in large cohorts of patients, but were only present in 6% of the entire cohort. ASLX1 mutations were present in 31% of MF patients and seemed to particularly associate with JAK2V617F negative status but not with a different prognosis of other features of the disease.

DNMT3A mutations were found across the entire spectrum of MPN, from ET and PV to MF and AML.

The 46/1 JAK2 haplotype predisposes to the development of JAK2 V617F–associated MPN, and its role in disease evolution was assessed. Researchers found that homozygosity of 46/1 was associated with a progressive increase in the JA2V617F allele burden.

In the non-malignant topics poster presentations, researchers found concluded that eculizumab was effective in reversing the thrombotic microangiopathy of atypical hemolytic uremic syndrome in patients who failed plasma exchange. Atypical hemolytic uremic syndrome results from uncontrolled complement activation, which may be specifically inhibited by eculizumab. Importantly, four of five patients who were dialysis dependent were able to come off dialysis. If confirmed, these findings will have important implications for the management of the condition, which has appeared in several outbreaks in Europe during the past few years.

Finally, in an intriguing but unexplained finding, French researchers studied hemochromatosis HFE gene mutations in high-level athletes in France. Researchers studied four groups. The first consisted of aerobic athletes, such as rowers and Nordic skiers. The second consisted of those who participate in anaerobic sports, such as judo. The third consisted of those who participate in non-energetic sports, such as petanque. The fourth was a suitable control group. A highly significant difference was found in the incidence of HFE mutations between energetic sports and controls but not between non-energetic sports. The difference was most marked in the group of athletes who participate in energetic sports and had won medals or titles. The difference was slightly more obvious in women compared with men.

Summary

Established therapies have the potential for dose manipulation without affecting efficacy, which may benefit older patients who often are excluded from randomized trials. Understanding the perturbation of homeostasis produced by genetic mutations in myeloproliferative and lymphoproliferative neoplasia greatly improves the prospects for specifically targeted therapies. Without doubt, the main theme and excitement of the meeting came from the clear signals that all the work on mechanisms of disease over the past decades, made possible by technological advances, is producing a real impact on treatment.

Edward Gordon-Smith, MD, MSc, FRCPath, is a professor at St. George’s Hospital Medical School in London. He also is a member of the HemOnc Today Editorial Board. He would like to thank Claire Harrison, MD, for her assistance in the compilation of this report. Disclosure: Dr. Gordon-Smith reports no relevant financial disclosures.

For more information:

• Hills RK. Blood. 2011;118:2389-2394.
• Lowenberg B. N Engl J Med. 2011;364:1027-1036.
• Presented at the European Haematology Association’s 16th annual congress in London; June 9-12, 2011:
• Andersen C. Abstract #1023.
• Angona A. Abstract #0918.
• Burgaleta C. Abstract #0923.
• Dine G. Abstract #0538.
• Harrison C. Abstract #1020.
• Kiladjian JJ. Abstracts #915 and #1062.
• Kluin-Nelemans H. Abstract #0504.
• Loriat C. Abstracts #0979 and #0980.
• Lowenberg B. Abstract #1019.
• Palumbo A. Abstract #0508.
• Scherber R. Abstract #0914.
• Schlenk R. Abstract #0906.
• Slot S. Abstract #0924.
• Stegelmann F. Abstract #1060).
• Tiacci E. Abstract #0509.
• Vannucchi A. Abstract #1021.
• Verstovsek, S. Abstract #0505.