The treatment of lymphoid malignancies is constantly evolving and improving. At the 2017 Annual EHA Congress many presentations reported on promising results from pre-clinical and clinical studies in patients with various lymphoid malignancies. A selection of the most valuable presentations is discussed below.
Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common cancer in children and differs from adult pre-B ALL in terms of incidence, driver mutations and prognosis. Although pre-B ALL is a heterogeneous malignancy, about a quarter of cases expresses the oncogenic ETV6-RUNX1 fusion protein as a result of the t(12;21) translocation. Since this translocation frequently occurs in utero, Dr Tariq Enver (University College London Cancer Institute, London, UK) and colleagues hypothesized that this initiating event arises in a target cell that is unique to early human development. “To address this hypothesis we searched for B-cell precursors in the human fetal liver (FL) and detected a population of CD19+IL7Rhigh pro-B-cells that emerged around day 41 post fertilization, and differentiated from CD19-IL7RhighKit+ progenitor cells. Gene expression profiling showed that during development these CD19-IL7RhighKit+ FL progenitor cells switched from myeloid to lymphoid lineage priming. Next, we observed that human induced pluripotent stem (hIPS) cells can generate IL7R+ progenitor cells with similar potential as their FL counterparts. When these hIPS were genetically engineered to express ETV6-RUNX1 they had a partial block in B-cell differentiation, and down-regulated their expression of B-cell receptors while up-regulating myeloid receptors. Furthermore, ETV6-RUNX1-containing, hIPS-derived CD34+ cells outcompeted wild type CD34+ precursor cells. Taken together, these results suggest that ETV6-RUNX1 initiates leukemia through lineage dysregulation of a lympho-myeloid series restricted to the first trimester of human development. This stalled differentiation may allow sustained RAG/AID activity thereby promoting additional driver events”, said Enver at the Plenary Session on Saturday.
There is accumulating evidence that in addition to oncogenic transcription factors extrinsic factors contribute to the development and survival of T-cell acute lymphoblastic leukemia (T-ALL). Here, Dr Françoise Pflumio (University of Paris, Fontenay-aux-Roses, France) and colleagues explored the development and resistance of T-ALL cells in bone marrow (BM) niches of the hematopoiesis rich and adipocyte poor thoracic vertebrae versus tail vertebrae that have a high adipocyte content but are low in hematopoiesis.1
“Our experiments in mice showed that both mouse and human T-ALL cells can infiltrate the vertebrae of the thorax and tail.2 Furthermore, the expression of many surface markers was lower on T-ALL cells recovered from the BM of tail vertebrae. This was not due to selection of genetically distinct T-ALL clones since molecular analyses showed that the T-ALL cells from both sites were genomically identical. Hence, we investigated if the two distinct BM environments influenced the T-ALL characteristics. Short-term, but not long-term, in vitro cultures demonstrated that T-ALL cells recovered from the tail vertebrae proliferated significantly slower than those from the thoracic vertebrae. In addition, in transfer experiments less T-ALL cells from thoracic BM versus tail BM were recovered from the femurs of secondary recipient mice. Interestingly, the phenotype of the T-ALL cells depended on the BM niche in which they infiltrated and not on the type of BM from which they were recovered before transfer”, said Pflumio.
Further research by Pflumio and colleagues showed that tail-derived T-ALL cells are metabolically less active, and have a lower glycolytic capacity and cell cycle progression than those recovered from the thorax. Moreover, tail-derived T-ALL cells are less sensitive to drugs that interfere with the cell-cycle. Finally, adipocytes were shown to induce a similar T-ALL phenotype en functioning as the BM from tail vertebrae.
Adult patients with acute lymphoblastic leukemia (ALL) have a very poor prognosis, with 5-year overall survival (OS) of around 7%.3 “To improve the outcome of these patients we successfully generated CD19-specific ’19-28z’ chimeric antigen receptor (CAR) T-cells and evaluated their activity in ALL-patients who were previously conditioned with chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T-cell infusion. Response assessment occurred at four weeks. Patients with less than 5% blasts were classified as minimal residual disease (MRD) cohort while patients with at least 5% blasts were allocated to a morphologic disease cohort”, said Dr Eric Smith (Memorial Sloan-Kettering Cancer Center, New York, USA).
In this phase 1 study a total of 53 patients with a median age of 44 was treated.4 The overall complete remission (CR) rate was 84.6% and the MRD-CR 66.6%. These CR rates did not differ by clinical subgroup based on for instance disease burden, age or conditioning regimen. Furthermore, the CR rates correlated with CAR T-cell expansion but not their infused dose. Smith: “The median event-free survival (EFS) was 6.1 months and the median OS 12.9 months in the overall population. Post-CAR T-cell allogeneic stem cell transplantation in seventeen patients did not impact EFS or OS in either the overall population, the MRD cohort or the morphologic disease cohort. Finally, adverse events (AEs) associated with the CAR T-cell transfer included cytokine release syndrome and neurological changes, which correlated with peak CAR T-cell expansion, and were less frequent among patients with MRD. Taken together, the early incorporation of 19-28z CAR T-cells in the frontline MRD setting may maximize their therapeutic efficacy while reducing their toxicity.”
Both the Bruton’s Tyrosine Kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax are registered as monotherapy for chronic lymphocytic leukemia (CLL). Since these two agents are hypothesized to have synergistic activity, their combined use could be associated with a favorable outcome in CLL.
The CLARITY trial is a feasibility study to investigate the safety and efficacy of ibrutinib combined with venetoclax in 50 patients with relapsed/refractory CLL. Patients were first treated with eight weeks of ibrutinib and subsequently with weekly escalating doses of venetoclax (10 mg > 400 mg) plus 420 mg ibrutinib. Next, patients were treated with 400 mg venetoclax and 420 mg ibrutinib up to 24 months or until MRD negativity for at least six months. The primary endpoint was MRD in the bone marrow after twelve months of treatment. Secondary endpoints included toxicity and progression-free survival.
At the Annual EHA Congress Dr Peter Hillmen (University of Leeds, Leeds, UK) reported on the safety of the combination treatment, as well as on early signs of their synergistic activity.5 “Common adverse events (AEs) of all grades included gastrointestinal disorders (n=101), musculoskeletal and connective tissue disorders (n=30) and nervous system disorders (n=25). The most frequently observed grade 3 or 4 AEs were neutropenia (n=15), infections and infestations (n=5) and metabolism and nutrition disorders (n=2). One case of a grade 3 tumor lysis syndrome (TLS) was observed following the 100 to 200 mg venetoclax escalation. Upon treatment the TLS resolved and the patient successfully escalated up to 400 mg venetoclax”, said Hillmen.
Among 18 patients with more than 10 x 109/L CLL cells in their blood, the CLL count increased during the initial eight weeks of ibrutinib monotherapy from a median of 50 x 109/L to 60 x 109/L. Then, during the first eight weeks of combination therapy the CLL count fell to 0.042 x 109/L.
Patients with advanced Hodgkin lymphoma (HL) can be effectively treated with eight or six cycles of eBEACOPP, although this intensive regimen is associated with severe toxicities. “To assess if patients can be treated with a less burdensome therapy, we investigated whether metabolic response determined by positron emission tomography after two cycles (PET-2) would allow us to select patients who could be treated with reduced intensity. For this purpose we conducted the randomized phase 3 HD18 trial in five European countries. Patients with newly diagnosed, advanced-stage HL and a negative PET-2 were randomly assigned to standard treatment with either six to eight cycles or four cycles of eBEACOPP”, said Dr Peter Borchmann (Uniklinik Köln, Cologne, Germany) at the Presidential Symposium.
The results demonstrated that PET-guided reduced therapy was non-inferior to intensive treatment in terms of five-year progression-free survival (92.2% versus 90.8%, difference +1.4%, 95% CI -2.7–5.4), and significantly superior regarding five-year overall survival (97.7% versus 95.4%, log-rank p=0.004).6 Moreover, reduced intensity treatment was associated with fewer severe infections (8% versus 15%) and organ toxicities (8% versus 18%), only two cases of acute myeloid leukemia, and no treatment-related mortality.
“These results demonstrate that treatment with only four cycles of eBEACOPP in patients with advanced HL and negative PET-2 is associated with a significant survival benefit. Furthermore, this reduced intensity treatment is safe, short and affordable. Therefore, we recommend PET-2-guided eBEACOPP for patients with advanced-stage HL”, said Borchmann.
Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis and a limited number of treatment options. CTL019 chimeric antigen receptor (CAR) T-cells represent a CD19-specific therapy currently evaluated in various R/R B-cell malignancies. Previous results from a single-center, phase 2 study showed durable remissions with a single infusion of CTL019 in R/R DLBCL.7
“JULIET is a global phase 2 trial investigating the efficacy and safety of CTL019 in adult patients with R/R DLBCL. The primary endpoint of the study was the best overall response rate (ORR). Key secondary endpoints were the duration of response (DOR), overall survival (OS) and safety. At the interim analysis the primary endpoint was met with a best ORR of 59%, including a complete response rate of 43%, among 51 evaluable patients.8 No significant differences in ORR were observed among relevant subgroups. The DOR was estimated at 79% relapse-free patients at six months. Furthermore, the median DOR and OS were not reached. Common adverse events (AEs) of special interest included cytokine release syndrome (all grades: 57%; grade 3-4: 26%), infections (27% and 13%) and cytopenias not resolved by day 28 (26% and 21%). AEs were generally reversible and effectively managed by appropriately trained study site personnel”, said Dr Gilles Salles (University of Lyon, Lyon, France) at EHA 2017.
Mantle cell lymphoma (MCL) is a rare but incurable type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation involving the IGH and CCND1 genes and leading to the overexpression of cyclin D1. “Although many MCL contain the t(11;14) translocation a group of cyclin D1-negative MCL-like lymphomas does not. Some of these lymphomas were shown to overexpress cyclin D2 or D3, in 55% of the cases due to rearrangement of the CCND2 gene.9,10 This rearrangement frequently involved the genes for the immunoglobulin light chains kappa and lambda.”, said Dr Sílvia Beà (IDIBAPS/CIBERONC, Barcelona, Spain) at the EHA Congress in Madrid.
The aim of the current study was to identify potential mechanisms driving the pathogenesis of cyclin D1 and D2-negative MCL-like lymphomas. Hereto, 66 cases with an MCL-morphology and phenotype were analyzed with various molecular techniques such as FISH and gene expression profiling.11 Beà: “By quantitative PCR we observed that 98% of the cases overexpressed the CCND2, D3 or E1/E2 cyclin genes. Remarkably, in 22% of the lymphomas with CCND2 overexpression and all of the cases with CCND3 or E1 overexpression a cyclin D gene rearrangement was lacking. Sequencing analyses showed that several lymphomas contained enhancer regions of the immunoglobulin genes inserted near the CCND2 and D3 genes, leading to their overexpression. These insertions might be used as diagnostic tools to recognize cyclin D1-negative MCL and may give us clues for other potential cryptic rearrangements in lymphomas with high protein expression but no conventional aberrations detected by FISH or karyotype.”
Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor (CAR) T-cell therapy that targets and eliminates CD19-expressing cells. ZUMA-1 is a multicenter phase 2 trial investigating axi-cel for the treatment of patients with refractory non-Hodgkin lymphoma (NHL), including diffuse large B cell lymphoma and primary mediastinal large B-cell lymphoma. The primary endpoint was the objective response rate tested in the first 92 patients treated. Key secondary endpoints were duration of response (DoR), overall survival (OS) and safety”, said presenting author Dr Yi Lin (Mayo Clinic, Rochester, USA) at a press briefing of the 22nd Congress of EHA.
The results showed that ZUMA-1 had met its primary endpoint with an ORR of 82%, including a complete response rate of 54%.12 Lin: “At a median follow-up of 8.7 months the median DoR was 8.2 months in the total population and not reached among patients with a complete response. The median OS was not reached. Furthermore, the treatment-associated toxicity was relatively low with grade ≥3 cytokine release syndrome and neurologic events occurring in 13% and 28% of patients, respectively. These adverse events were generally manageable and reversible. Thus, we consider axi-cel as a very promising treatment for patients with refractory, aggressive NHL.”
Gain of 1q is associated with a poor outcome in multiple myeloma (MM).14 However, although gain of 1q is considered as an oncogenic driver, the underlying molecular mechanisms are poorly understood. The current study by Dr Fengyan Jin (Jilin University, Changchun, China) and colleagues aimed at gaining more insight into these mechanisms. They observed that MM cells carrying three or more copies of 1q expressed extremely high levels of the hypoxia-inducible transcription factor HIF-1b.15 Moreover, expression of HIF-1b correlated with MM progression and high expression was associated with a poor prognosis of MM patients. In addition, the expression of HIF-1b was higher in high-risk MM subtypes than in other subtypes. Next, Jin and colleagues evaluated the relation between hypoxia and the expression of HIF-1b in MM cells. “We observed that hypoxia or its chemical mimetic lactic acid induced HIF-1b expression and NF-kB activation, which was associated with resistance to bortezomib. In addition, HIF-1b expression was increased in MM cells that acquired resistance to bortezomib or lenalidomide, a phenotype that was reversed upon inhibition of HIF-1b expression. Finally, our results demonstrated that HIF-1b expression correlates with that of TRAF2, a key component of the NF-kB signaling pathway. In addition, inhibition of NF-kB blocked the expression of HIF-1b, suggesting that expression of HIF-1b depends on the activation of NF-kB. Taken together, overexpression of HIF-1b or amplification of its gene might serve as a novel marker for risk stratification as well as a therapeutic target in MM patients, especially those with high-risk cytogenetics such as gain of 1q”, said Jin at the EHA Congress.
Bortezomib is an effective treatment for amyloid light-chain (AL) amyloidosis. However, as yet, no prospective results from multicenter studies on the use of bortezomib induction treatment before autologous stem cell transplantation (ASCT) have been reported. At EHA 2017 Dr Monique Minnema (University Medical Center Utrecht, Utrecht, The Netherlands) presented the final results of the HOVON 104 study which evaluated the outcome of bortezomib plus dexamethasone induction therapy followed by ASCT in adult patients with de novo AL amyloidosis.16 The primary aim of the study was to improve the hematological complete response (CR) rate at six months after ASCT from 30% to 50% in the intention-to-treat (ITT) population.
The study enrolled 50 patients with a median age of 59. “The bortezomib-based induction treatment was associated with several adverse events (AEs), including metabolic and nutrition AEs (42% grade 3-4), infections (30% grade 3-4) and gastrointestinal AEs (28% grade 3-4). Due to these side effects dose adjustments were made for bortezomib in 50% of the total cycles and for dexamethasone in 42% of the cycles. Six patients received less than four cycles of bortezomib/dexamethasone and fifteen patients did not proceed to ASCT. One patient died after ASCT, resulting in a treatment-related mortality (TRM) rate of 3%. Furthermore, the overall hematological response was 80% after both induction therapy and ASCT. The CR rate increased from 6% following induction treatment to 43% six months after ASCT. However, the CR rate in the ITT population was only 30%, and therefore the primary endpoint of this trial was not met. This was likely due to the high dropout rate between induction treatment and ASCT. Furthermore, the response rates of the kidney, heart and liver after induction treatment and after ASCT increased form 24% to 55%, from 21% to 57%, and from 15% to 25%, respectively. Taken together, induction treatment before ASCT is associated with a low TRM rate, but may put patients at risk for not being transplanted.”