Peter D. Emanuel

Key Points: Early postnatal loss of Pten protein in mice with Nf1 haploinsufficiency causes a fatal juvenile myeloproliferative neoplasm. Akt and MAPK activities are elevated in juvenile mice with Nf1 haploinsufficiency and Pten protein loss.

Key Points: Mutations in SETBP1 can be detected using droplet digital polymerase chain reaction in at least 30% of patients with JMML and are associated with a dismal prognosis. Patients harboring rare cells with mutant SETBP1 at diagnosis should be considered candidates for swift hematopoietic stem cell transplant.

The disease spectrum currently known as the proteasome‐associated autoinflammatory syndromes (PRAAS) was first described in 1939 in patients who presented with recurrent fevers beginning in infancy or early childhood, which were accompanied by nodular erythema, a pernio‐like rash, and joint contractures. Since then, several syndromes, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Nakajo–Nishimura syndrome (NNS), joint contractures, muscle atrophy, microcytic anemia and panniculitis‐induced lipodystrophy (JMP) syndrome, and Japanese autoinflammatory syndrome with lipodystrophy (JASL), have been used to categorize patients with diseases within the same spectrum. Recently, independent studies have identified mutations in the human proteasome subunit β type 8 (PSMB8) gene, which result in a sustained inflammatory response in all syndromes. Further functional studies not only suggest a causative role of PSMB8 mutations but also imply that they represent one disease spectrum, referred to as PRAAS. In this paper, we review the clinical presentations and laboratory findings of PRAAS, as well as the most recent advances in pathogeneses, diagnosis, and treatment options for patients with diseases in this spectrum.

Background Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13‐cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. Procedure Eighty‐five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty‐seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty‐eight patients enrolled only in the phase III trial. Results Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre‐transplant toxicities. Forty‐six percent of the 44 patients who received protocol compliant HSCT relapsed. Five‐year overall survival was 55 ± 11% and event‐free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib. Conclusions Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long‐term overall survival. Pediatr Blood Cancer 2015;62:629–636.

In this issue of Blood, Goodwin et al investigate the pathogenesis of juvenile myelomonocytic leukemia (JMML), demonstrating that mutant Shp2 induces granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity and that the p110δ subunit of phosphatidylinositol 3-kinase (PI3K) further promotes this dysregulation

Summary: The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP‐CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP‐CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4‐log reduction of BCR‐ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3‐log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR‐ABL1 levels in the IM800 arm were an average 2·9–fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression‐free (P = 0·048) and relapse‐free (P = 0·031) survival were superior for IM800. In newly diagnosed CP‐CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression‐free and overall survival, but was associated with more severe toxicity.