Riad El Fakih

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation

High‐dose, post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1‐antigen human leukocyte antigen (HLA)‐mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients.

FLT3 Inhibitors for Treating Acute Myeloid Leukemia

FLT3 (Fms-like tyrosine kinase 3) inhibitors are tyrosine kinase inhibitors. The first-generation FLT3 inhibitors were developed several years ago and include midostaurin, lestaurtinib, sunitinib, and sorafenib. They are relatively nonspecific for FLT3, with other potential targets that include platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and Janus kinase 2. The second-generation inhibitors, including quizartinib, crenolanib, PLX3397, and ASP2215, are more potent and selective than the first-generation inhibitors. The greater potency and selectivity promises greater efficacy in FLT3-mutated acute myelogenous leukemia (AML) (particularly in patients with a greater allele burden) and less toxicity. A number of receptor tyrosine kinase inhibitors are being studied across virtually all disease settings, including frontline, relapsed and refractory, and maintenance, mainly in patients with FLT3-mutated AML. The future of FLT3 inhibitors in the treatment of AML, in combination with chemotherapy or stem cell transplant, appears bright. The present report reviews the current data on FLT3 inhibitors.

Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults

Philadelphia chromosome‐positive (Ph‐positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor‐B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR‐ABL1 or a p190 BCR‐ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self‐renewal, leading to leukemogenesis. In Ph‐positive ALL, the p190‐BCR‐ABL (minor [m]‐bcr) subtype is more frequent than the p210‐BCR‐ABL (major [M]‐bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo‐HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph‐positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo‐HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.

Hematidrosis: A Fascinating Phenomenon—Case Study and Overview of the Literature

As previously explored in this journal, the investigation of bleeding symptoms involves a systematic investigative approach that includes investigation of patient and family history, physical examination, and laboratory testing.1 Although this is also true of an investigation into pediatric bleeding, there are special considerations required, including the reduced period of capture for personal history, and fewer hemostatic challenges.2 Sometimes, such investigations prove fruitless and do not uncover a true bleeding diathesis. Hematidrosis is one such example. Hematidrosis is a fascinating disorder characterized by blood oozing from the intact skin and mucous membranes in the absence of a bleeding problem. It frequently affects young girls (i.e., typically between 9 and 13 years) under stressful situations, and probably suffering from an underlying anxiety disorder. These patients usually undergo a thorough and expensive hematology evaluation aimed to identify a possible underlying bleeding disorder, but which fails to provide the answer. Here, we report a case of a 9-year-old girl exposed to bullying at school, which leads to recurrent bleeding episodes. The young patient had no prior medical or psychological illness and presented to our clinic following a 5-month history of recurrent spontaneous blood loss from skin, scalp, ear, mouth, and eyes (►Fig. 1). Her parents claimed that the episodes happen twice weekly on average, mostly in the evening, and with no clear precipitating factors. Each episode lasted for 1 or 2 minutes and was usually self-limited. Family history was negative for any bleeding disorders. She was evaluated by her family physician and a local hematologist, and aworkup for commonbleeding disorderswas unrevealing (►Table 1). The patient also underwent upper gastrointestinal endoscopy because some of these episodeswere accompanied by bleeding from her mouth. The endoscopy and biopsy were consistent with celiac disease, which was later confirmed by serological testing. Nevertheless, no clinical signs of celiac disease could be recorded. Upon her evaluation in our clinic, her vital signs and growth chart were within normal limits, and physical examination was unrevealing; specifically, there were no signs of self or secondary-inflicted injuries (scars, fresh cuts, scratches, or wounds). On further questioning, the parents reported that these episodes did not occur on holidays and usually happened on the days she attended school. The patient admitted that she always felt intimidated and emotionally abused by her school colleagues. A sampling of the fluid discharge confirmed the presence of red andwhite blood cells along with epithelial cells. Hematohidrosis or hematidrosis is a rare and largely mysterious phenomenon, with only a few case reports having been published.3–14 Reported patients are usually young girls,3,5 and present with blood oozing from intact skin or mucous membranes in the setting of stress and anxiety.11 The episodes last for few minutes,3 and resolve almost spontaneously.5 Theworkup for bleeding disorders is usually normal, and the examination of the bloody fluid demonstrates the presence of blood elements. It is important to carefully examine the skin to rule out self-inflicted or secondary injuries (e.g., potentially pointing to Munchausen’s syndrome or Munchausen’s by proxy) and to also differentiate this entity from chromhidrosis (color pigment in sweat), vasculitis, scurvy, or other connective tissue disorders (where vascular fragility can lead to easy bleeding). Some of the reported cases underwent biopsy of the oozing areas with active bleeding and did not show any histopathological findings.4,5 Although the frightening presentation of hematidrosis leads to immediate medical evaluation in most of the cases, the diagnosis is often delayed because the condition is a rare and frequently overlooked phenomenon. Frequently, patients will have extensive evaluations including hematology consultation before reaching a correct diagnosis. The etiology remainsmostly unknown. Stress-induced vasoconstriction (through adrenergic stimulation) in the small blood vessels around the sweat glands and eventually leading to vascular rupture and blood extravasationwith the sweat is the proposed cause.10,11 The fact that most cases

Outcome of Patients with Immunoglobulin Light-Chain Amyloidosis with Lung, Liver, Gastrointestinal, Neurologic, and Soft Tissue Involvement after Autologous Hematopoietic Stem Cell Transplantation.

There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.

A case of T-cell lymphoproliferative disorder associated with hypereosinophilia with excellent response to mycophenolate mofetil.

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by a persistent elevation of blood eosinophil count ⩾1.5×109/L and clinical manifestations attributable to eosinophilia or tissue hypereosinophilia. Lymphocytic variant of HES (HES-L) is a known subtype according to World Health Organization classification. It is well documented in the literature that patients with HES-L are predisposed to develop T-cell lymphoma. We report a case of T-cell lymphoproliferation associated with hypereosinophilia, which has been successfully treated with mycophenolate mofetil, with resolution of skin lesions and normalization of eosinophil count and immunoglobulin E level. We believe this is a clinically relevant case since this is a rare disease with little known knowledge on its best treatment modality.

Refining the Role of Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia as Novel Therapies Emerge

Acute lymphoblastic leukemia (ALL) is a rare adult neoplasm. The disorder consists of precursor B or T phenotypes. In the pediatric population, ALL was a success story in that 80% of children with ALL enjoy long-term survival. In adults, similar complete remission rates are achieved with current induction regimens; however, less than 50% of patients are alive at 5 years, with most deaths due to relapsed disease. Accordingly, optimizing post remission consolidation therapy might improve in outcomes. Such strategies may include chemotherapy and autologous or allogeneic transplant. Moreover, the ability to modify such therapy based on better disease risk stratification while taking into account patient characteristics such as performance status and presence of comorbidities is necessary to tailor treatment accordingly. Here, we review available medical literature on the use of hematopoietic cell transplantation as a consolidation modality in the treatment of adult ALL.

5-Azacitidine for treating acute myelogenous leukemia

Introduction: 5-Azacytidine is a chemically synthesized nucleoside analogue that was manufactured in the 1960s. It is a DNA methyltransferase (DNMT) inhibitor that has in vitro and in vivo demethylating effects. On 19 May 2004, the US FDA approved azacitidine as injectable suspension for treatment of patients with myelodysplastic syndromes (MDS).Areas covered: Hypomethylating therapy has been increasingly used in place of standard intensive chemotherapy for the treatment of ‘unfit’ elderly patients with acute myeloid leukemia (AML). In the USA, azacitidine and decitabine are the most commonly used low-intensity therapies. In this article, we review the current literature about azacitidine for the treatment of MDS, AML and in the stem cell transplant field.Expert opinion: Azacitidine is an old/new drug that gained more attention after its FDA approval for MDS. It is the only drug that showed survival benefit in MDS, in a Phase III randomized controlled trial. Azacitidine also has an important role in treat...

Philadelphia chromosome-positive lymphoblastic lymphoma—Is it rare or underdiagnosed?

Lymphoblastic lymphomas (LBLs) are neoplasms of precursor B and T cells; they are considered in the same spectrum as precursor B and T cell acute lymphoblastic leukemia (ALL). The World Health Organization classification classifies both LBL and ALL as one disease entity. While chromosome abnormalities are well defined with all of their therapeutic and prognostic implications in ALL, these are not well studied in LBL. Here, we describe a case of Philadelphia chromosome-positive LBL and review the available literature regarding this entity.

Philadelphia-Like acute lymphoblastic leukemia: diagnostic dilemma and management perspectives

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAK/STAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method. Accurate and standard testing approaches are much needed and this will facilitate better understanding of this subgroup, including better estimation of the prevalence and incidence in different age groups and the clinical outcomes of such new entity. Here, we review the currently available diagnostic tools, activated pathways, and different therapeutic approaches used to target this subgroup.