Late-Breaking Abstracts Presented at ASH 2016

By Lynne Lederman, PhD

At this past December’s American Society of Hematology (ASH) annual meeting, the late-breaking abstract (LBA) session was devoted to presentations selected by the Program Committee for featuring substantive, novel, and groundbreaking data that were not available by the general abstract submission deadline and would not otherwise have been presented at the meeting.

The presentation on phase 2 results of the ZUMA-1 trial of the chimeric antigen receptor (CAR) therapy KTE-C19 (axicabtagene ciloleucel) in patients with chemotherapy-refractory diffuse large B-cell lymphoma1 has attracted a lot of attention.2

Here we report on 4 other presentations in the LBA session that are also likely to affect the outcome of patients with cancer in the future.

Adding Consolidation or Second Transplant to Single Transplant and Maintenance Does Not Improve Outcomes in Multiple Myeloma

Edward A. Stadtmauer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, presented primary results from the randomized, prospective phase 3 trials of the Bone and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 STaMINA trial (NCT01109004).3

This trial investigated whether the addition of a second autologous hematopoietic stem cell transplant (AHCT) or consolidation therapy combining a proteasome inhibitor (PI) with an immunomodulatory agent (IMiD) to upfront treatment of multiple myeloma (MM) with AHCT plus lenalidomide maintenance would provide additional benefit.

The study enrolled transplant-eligible patients with symptomatic MM who were age £70 years within 2 to 12 months of initiating ³2 cycles of systemic therapy, without prior disease progression, who had sufficient autologous stem cells available. Patients (N=758) were randomly assigned to receive:

  • Melphalan 200 mg/m2 AHCT and 4 cycles of consolidation therapy (lenalidomide 15 mg daily on days 1 to 14; dexamethasone 40 mg days 1, 8, and 15; and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle) (ACM) (n=254) OR
  • Tandem melphalan 200 mg/m2 AHCT (n=247) OR
  • A single AHCT (n=257)

All patients also received maintenance therapy with lenalidomide, initially at 10 mg/day for 3 cycles, then 5 to 15 mg/day for 3 years as tolerated. In 2014 an amendment to the protocol allowed maintenance therapy to continue for an indefinite duration until disease progression.

The primary objective was to compare 38-month progression-free survival (PFS) of patients in the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. The 38-month period allowed 2 months to obtain the first transplant plus 3 years of follow-up.

Secondary endpoints in all 3 arms included overall survival (OS); response rates; rate of conversion to complete response (CR) for patients who did not have CR; toxicity, including infections, after each intervention and long-term toxicity; rate of non-compliance with protocol therapy; treatment-related mortality; and quality of life (QoL).

Enrollment was completed ahead of the projected time. Patients were stratified by risk, with high-risk MM defined by high beta-2 microglobulin and high risk cytogenetic abnormalities. Demographics were balanced across the groups. Over 90% of patients had either a proteasome inhibitor (PI) or immunomodulatory drug (IMiD) as initial therapy, and over 50% had both. The median follow-up time for myeloma status was 37.8 months.

The second AHCT was not administered to 32.0% in the tandem AHCT arm; 11.8% of patients in the AHCT/consolidation arm did not receive consolidation. Maintenance therapy was not started in 16.6% and 16.9% of patients in these arms, respectively, whereas only 5.4% of patients in the single AHCT arm did not receive maintenance.

There was no difference in the primary endpoint, PFS, among arms, with a 38-month estimate of PFS of 56.5 months in the tandem transplant arm, 56.7 months in the transplant/consolidation arm, and 52.2 months in the single transplant arm. Likewise, there was no significant difference in OS among the groups (82.0, 85.7, and 83.4 months, respectively), or in PFS or OS for patients with either standard-risk or high-risk MM.

Treatment-related mortality was low: 4 deaths in the tandem group, 3 in the consolidation group, and 1 in the single transplant group. Secondary primary malignancies were reported in all arms (5.1% in the total population; 14, 15, and 10, incidents respectively),

This trial is the largest randomized comparison of post-transplant approaches for MM in the United States. It shows that after initial therapy with PIs and IMiDs, an initial AHCT, and prolonged lenalidomide maintenance therapy, the addition of consolidation therapy with bortezomib, lenalidomide, and dexamethasone after transplant or use of a second transplant do not produce incremental PFS benefits.

These results also show that induction triplet therapy containing a PI and IMiD followed by a single transplant is sufficient, and may spare patients the additional burden of a second transplant or consolidation.

Companion protocols to this trial include BMT CTN 07LT, which continues long-term follow-up and maintenance therapy to patients in the original trials who completed 3 years of maintenance therapy without disease progression. An analysis including PFS, OS, second primary malignancies, event-free survival, and quality of life (QoL) will be conducted when all surviving patients are >5 years post-randomization, which is expected around 2018.

The PRiMER protocol adds a minimal residual disease (MRD) assessment by flow, and correlative analyses of bone marrow and blood samples to be conducted in 2017. MRD assessment by gene sequencing is on-going.

Newly Identified Mutations Increase Risk for Hereditary ALL

Inherited mutations in the gene IKZF1 are associated with increased risk of developing childhood acute lymphocytic anemia (ALL), the most common childhood cancer, and a leading cause of cancer-related death in children. Both common and rare germline variants have been previously reported to be associated with inherited risk of childhood ALL.

Michelle L. Churchman, PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, reported on identification of a germline mutation in the IKZF1 gene that is associated with multiple cases of childhood ALL in a single famliy.4

The IKZF1 gene encodes the protein Ikaros, a member of the family of zinc finger transcription factors, which plays a role in lymphocyte development. Analysis of members of this family suggested that an inherited mutation in IKZF1 was associated with ALL.

The aims of this project were to determine the prevalence of inherited IKZF1 variants in ALL, and to determine if germline variants affect the function of IKZF1.

Germline DNA from 4,957 patients with sporadic ALL enrolled in frontline trials of St. Jude Children’s Research Hospital and the Children’s Oncology Group was subjected to targeted IKZF1 next-generation sequencing.

Common variants, non-coding, and synonymous variants were excluded; 44 patients were found to have germline IKZF1 mutations, of which 27 were unique variants.

These unique variants were shown to de-repress transcriptional targets, deregulate adhesion molecule expression leading to aberrant cell-stroma adhesion in the bone marrow in vivo, and conferred reduced response to treatment with dexamethasone and dasatinib in vitro and in vivo.

The results identify IKZF1 as a new ALL predisposition gene, and that germline variants play a role in the pathogenesis of ALL and response to therapy. An important question to answer is whether or not germline IKZF1 variants can be used to predict prognosis in ALL.

Ibrutinib Resolves Steroid-Resistant GVHD

Chronic graft-versus-host disease (cGVHD) is the most common cause of morbidity in patients who have received an allogeneic stem cell transplant. There are no approved treatments for cGVHD that is unresponsive to corticosteroids. David Miklos, MD, Stanford University, Stanford, California, presented the results of a multicenter, open-label, phase 2 study of ibrutinib in patients whose cGVHD failed to respond to corticosteroids and were in need of further treatment (PCYC-1129; NCT02195869).5

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) that also inhibits interleukin-2 (IL-2)-inducible T-cell kinase (ITK), and has been approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), including CLL/SLL with 17p deletion, Waldentrom’s macroglobulinemia, and mantle cell lymphoma that has been treated with at least 1 prior therapy.6

Ibrutinib had been shown to reduce the severity of cGVHD in preclinical models and early clinical studies. Early results from the study supported the designation of ibrutinib as breakthrough therapy for cGVHD after failure of one or more lines of systemic therapy.7

The study enrolled patients with cGVHD that had failed £3 prior lines of therapy who had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4.

Ibrutinib was given orally at 420 mg until progression of cGVHD or unacceptable toxicity. The primary endpoint was response per the 2005 NIH consensus response criteria. Secondary endpoints included rate of sustained response, change in symptoms and corticosteroid requirements, and safety. Additional exploratory endpoints included effects on lymphoid and myeloid signaling pathways and plasma cytokines and chemokines.

The 42 enrolled patients had myeloablative (43%) or non-myeloablative (57%) transplants from related (40%) or non-related (60%) donors. Most had matched peripheral stem cells. Indications included acute and chronic anemias and other hematologic malignancies. All had prior corticosteroid, with a median of 2 prior regimens.

At a median follow-up of 14 months, 29% of patients were still taking ibrutinib; adverse events were the most frequent cause of discontinuation (33%).

Adverse events (AEs) were consistent with those reported for B cell malignancies treated with ibrutinib and those observed in patients with cGVHD treated with corticosteroids, and included fatigue, diarrhea, muscle spasms, nausea, and bruising.

Serious AEs occurred in 52% of patients including pneumonia, septic shock, and fever; 2 deaths due to multilobular pneumonia and bronchopulmonary aspergillosis occurred. Dr. Miklos commented that the lack of cardiac complications might be attributed to the small patient population.

A complete response (CR) (defined as complete resolution of all reversible manifestations of cGVHD) was observed in 9 patients; the overall response rate was 67% (CR plus partial response); 71% of the 28 patients with complete or partial responses had a sustained response for at least 5 months.

Responses were observed across multiple affected organs including skin, mouth, liver, and gastrointestinal tract, and patients with multiple organ involvement generally had responses in 2 or more organs. Overall, 62% (n=26) of patients had corticosteroid doses of <0.15 mg/kg daily, representing a reduction in corticosteroid use, during the study, and 5 discontinued all corticosteroids.

Soluble plasma factors related to inflammation, fibrosis, and cGVHD, such as pro-inflammatory cytokines, chemokines, and tissue growth factors, including tumor-necrosis factor alfa, interleukins, and epidermal growth factor, decreased with ibrutinib therapy.

These results support the investigation of ibrutinib for the front-line treatment of cGVHD in a randomized, double-blind study that is on-going.8

Pacritinib Benefits Patients with Myelofibrosis

John Mascarenhas, MD, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, presented the results of the PERSIST-2, open-label, phase 3 study, which compared the safety and efficacy of pacritinib (200 mg twice daily or 400 mg once daily) to currently available therapies, including ruxolitinib, in patients with myelofibrosis who had platelet counts of £100,00 per microliter.

Ruxolitinib is a Janus kinase (JAK1/2) inhibitor, approved by the FDA in 2011 to treat intermediate- or high-risk myelofibrosis, which is a life-threatening condition. Ruxolitinib reduces splenomegaly and myelofibrosis symptoms, but causes dose-limiting cytopenias, and is not indicated for those with platelet counts <50,000 per microliter.10 Therefore, individuals with myelofibrosis and severe thrombocytopenia represent a population with unmet needs.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, and other enzymes, and reduced spleen volume and controlled symptoms of myelofibrosis compared with best available therapy (BAT excluding JAK2 inhibitors) regardless of platelet count.

Pacritinib was placed on full clinical hold by the FDA on February 8, 2016 due to concerns about interim survival results, bleeding, and cardiovascular events. The trial was shortened due to the clinical hold.11 However, the hold was recently lifted, and a new trial is set to begin that is enrolling as many as 105 participants with primary myelofibrosis who have failed previous ruxolitinib therapy.12

Of patients enrolled in the pacritinib once daily (n=104), pacritinib twice daily (n=107) or BAT (n=100) groups, nearly all discontinued treatment, mostly due to the clinical hold.

Analyses were done at week 24 prior to the hold. Half the patients in the BAT had crossed over to pacritinib treatment. BAT had consisted of ruxolitinib (45%), hydroxyurea (19%), or “watch and wait” (19%).

Pacritinib was associated with statistically significant reduction in spleen volume vs BAT (P=.001 vs pacritinib groups combined, P=.017 vs once daily, P=.001 vs twice daily).

The twice daily dose of pacritinib was associated with significant ≥50% reduction in total symptom score vs BAT, whereas the once daily dose was not. This may be due to higher steady-state plasma levels associated with the twice daily dose.

Platelet count in patients with a baseline platelet count of <50,000 per microliter increased in both pacritinib groups, and to a greater extent in the once daily group.

Patients treated with pacritinib also had lower requirements for red blood cell transfusion that those in the BAT group at weeks 12 and 24. OS for the pacritinib groups and the BAT group censored at the date of clinical hold were not significantly different.

Pacritinib was associated with more AEs than BAT, primarily diarrhea, nausea, vomiting, anemia, and thrombocytopenia, and were generally less frequent with twice daily dosing. Deaths due to AEs and/or progressive disease occurred in all groups at about the same rate.

In the discussion that followed his presentation, Dr. Mascarenhas said pacritinib was well tolerated and offered symptom relief in a patient population that was quite ill. He continued that his opinion as a clinical investigator is that pacritinib is an effective drug, with a benefit-risk ratio in its favor, and he hopes to see the drug move forward, although additional trials will require FDA approval.



  1. Neelapu SS, Locke FL, Bartlett NL, et al. Kte-C19 (anti-CD19 CAR T Cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 Zuma-1. Blood 2016 128:LBA-6.
  2. Wolfe G, Grisolano J. CARs of the future on display at ASH 2016 as ZUMA-1 wows the crowd. The OBR Blog.
  3. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem autoHCT with Len maintenance (TAM) and autoHCT with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). Blood 2016 128:LBA-1.
  4. Churchman ML, Qian M, Zhang R, et al. Germline genetic variation in IKZF1 and predisposition to childhood acute lymphoblastic leukemia. Blood 2016 128:LBA-2.
  5. Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Blood 2016 128:LBA-3.
  6. Imbruvica® (ibrutinib) capsules, for oral use. Prescribing information. Pharmacyclics, LLC, Sunnyvale, California. June, 2016.
  7. Ibrutinib (IMBRUVICA®) Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for the Development of a Treatment for Chronic Graft-Versus-Host Disease (CGVHD).; 2016. Available at: Accessed January 9, 2017.
  8. Ibrutinib in Combination with Corticosteroids versus Placebo in Combination with Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease (cGVHD) (iNTEGRATE). Accessed January 9, 2017.
  9. Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the Persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Blood 2016 128:LBA-5.
  10. Jakafi® (ruxolitinib) tablets for oral use. Prescribing information. Incyte Corporation, Wilmington, Delaware. March 2016.
  11. Adams B. Struggling CTI reveals new pacritinb data, misses a primary endpoint. August 29, 2016. Accessed January 5, 2017.
  12. PR Newswire. CTI BioPharma Announces Removal of Full Clinical Hold On Pacritinib. January 5, 2017. Accessed January 9, 2017.


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