Red and white cell disorders

At the 22nd Congress of EHA, clinical trial results of three promising therapies were shared. These include an exciting gene-corrected hematopoietic stem cell transplantation approach for fanconi anemia patients, a phase 2 trial with luspatercept in β-thalassemia patients and subgroup analyses of crizanlizumab in sickle cell patients. Although these therapies are still being carefully evaluated for their clinical efficacy and safety, they are likely candidates to treat specific blood diseases in the future.

Promising autologous gene-corrected HSC transplantation in Fanconi anemia

Today, treatment of patients with Fanconi anemia (FA) is based on allogeneic hematopoietic stem cell (HSC) transplantation. Autologous gene-corrected HSC transplantation has previously been exploited with disappointing results, “probably due to the low number of stem cells collected to transduce and the quality of the vector” said Dr Julián Sevilla (Hospital Infantil Universitario Niño Jesús, Madrid, Spain).

Interested in the webcast of Dr Sevilla's presentation on Fanconi anemia?

To improve these results, Sevilla developed two optimized trials in which HSC cells are collected in an early stage of disease and infused back later.1 These regimes include mobilization of HSCs with 4 doses of plerixafor and high-dose G-CSF before harvesting, selection for CD34+ HSC and subsequent retransfusion (FANCOSTEM). In the FANCOLEN trial, these collected CD34+ cells were transduced with a short protocol involving a new PGKFANCA:LV lentiviral vector, and then eventually were retransfused without any conditioning regimen.  

So far, 10 patients are included in FANCOSTEM and all but two patients had sufficient numbers of mobilized cells to continue HSC collection by leukoapheresis. After leukoapheresis, the yield of CD34+ cells was clearly higher than in previous trials. However, on average >50% of cells were lost with CD34 selection, and the magnitude of this loss was rather heterogeneous. FANCOLEN enclosed 4 patients up to now and none experienced severe adverse events in 5-17 months. Although numbers of infused CD34+ cells were extremely low, all patients showed engraftment, and in one patient the presence of gene-corrected hematological cells could be demonstrated.

Based on these data, Sevilla concluded stating that this protocol of transplantation of autologous, gene-corrected HSC for the first time provides evidence of a repopulation advantage of gene-corrected HSCs even in non-conditioned FA patients. This strategy appeared so far to be safe and efficient, although longer follow-up is essential to confirm its efficacy. 

Luspatercept continues to phase 3 in β-thalassemia

The TGFβ superfamily represent powerful endogenous inhibitors of late stage erythropoiesis. It was hypothesized that modifying this signalling pathway would be beneficial for patients with inherited β-thalassemia, and to this end luspatercept (ACE-536) has been developed. Indeed, preclinical and clinical phase 1 data proved that it was able to correct ineffective hematopoiesis and increase hemoglobin levels, and it was well tolerated.2,3 Consequently, an open-label phase 2 trial was initiated, in which either transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thalassemia patients receive luspatercept every 3 weeks subcutaneously, with a maximum of five doses.4 In this still ongoing trial, patients are subdivided into 6 cohorts receiving 0.2-1.25 mg/kg doses (base cohort). Sixty-four patients enrolled, and 51 continued to a long extension study, in which they were treated with ≥0.8 mg/kg with titration to 1.25 mg/kg.

In this trial, treatment reached relevant clinical significance, as during a 12-week period the transfusion burden was >50% decreased in 55% of TD patients of the base cohort and in 71% of the extended cohort. Furthermore, when treated with ≥0.6 mg/kg, hemoglobin levels increased with more than 1.5 g/dL in 33% and 52% of NTD patients from the base and extension cohort, respectively. Interestingly, these improvements correlated with a better quality of life and only a few grade 3 related adverse events occurred.

Therefore, these data indicate that luspatercept treatment in TD and NTD β-thalassemia patients shows clinically meaningful efficacy, while safe and well tolerated. These data led to a phase 3, double-blinded, placebo-controlled study that is currently ongoing in TD patients.

Crizanlizumab effective in all sickle cell subgroups

Sickle cell-related pain crises (SCPCs) substantially contribute to morbidity numbers of sickle cell disease patients. There is accumulating evidence showing that the protein P-selectin is involved in initiating this crisis, and this led to the idea that inhibiting P-selectin would decrease the number of SCPC events. Therefore, the humanized P-selectin antibody crizanlizumab has been developed, which significantly reduced the number of SCPC events in sickle-cell patients included in the 52-week phase 2 SUSTAIN trial.5

In this trial, adults who experienced 2-10 SCPC events in the previous 12 months received either 2.5 or 5.0 mg/kg crizanlizumab or placebo. To evaluate the characteristics of those patients who did not experience an SCPC event, Dr Abdullah Kutlar (Augusta University, Augusta, USA) performed a post-hoc analysis of the intent-to-treat population.

Almost twice as many patients in the 5.0 mg/kg group (35.8%) did not experience any crisis, compared to the 2.5 mg/kg (18.2%) or placebo groups (16.9%). This trend was apparent in all subgroups analysed. Whereas the number of event-free patients did not depend on the number of prior events, the absence of events tended to occur more often in patients with a phenotype other than homozygous (HbSS) and in patients who did not receive hydroxyurea.

As the benefits of crizanlizumab were persistent in all subgroups investigated, including those at higher risk of experiencing an SCPC event, Kutlar emphasized that “crizanlizumab at 5 mg/kg is definitely a candidate to meet an unmet need as an effective treatment that can keep patients crisis-free.”


  1. Sevilla J, et al. EHA 2017: abstract S144.
  2. Suragani R, et al. Blood. 2014 Jun 19;123(25):3864-72.
  3. Attie K, et al. Am J Hematol. 2014 Jul;89(7):766-70.
  4. Piga A, et al. EHA 2017: abstract S129.
  5. Ataga KI, et al. N Engl J Med 2017;376:429-439.
  6. Kutlar A, et al. EHA 2017: abstract S454.