How and when should we monitor chimerism after allogeneic stem cell transplantation?

Summary:Chimerism analysis has become an important tool for the peri-transplant surveillance of engraftment. It offers the possibility to realize impending graft rejection and can serve as an indicator for the recurrence of the underlying malignant or nonmalignant disease. Most recently, these investigations have become the basis for treatment intervention, for example, to avoid graft rejection, to maintain engraftment and to treat imminent relapse by pre-emptive immunotherapy. This invited review focuses on the clinical implications of characterization of hematopoietic chimerism in stem cell transplantation.     

Haematopoeitic cell transplantation for Fanconi anaemia – when and how?

Allogeneic haematopoietic cell transplantation (HCT) remains the only treatment that can correct the haematological manifestations in patients with Fanconi anaemia. Over the last two decades, sequential changes to the approach to HCT have resulted in reduced regimen‐related toxicity, superior engraftment and less graft‐versus‐host disease (GVHD), resulting in improved survival. The two pivotal changes that most influenced these improvements were the addition of fludarabine to the preparative regimen to augment engraftment, and the use of T cell depletion to reduce GVHD. With these improved HCT outcomes, indications for HCT are quite consistent regardless of donor source. Emphasis is now being placed on developing HCT regimens that will improve quality of life by reducing late effects, particularly the risk of malignancy, sterility and endocrinopathies. This paper will review the unique challenges of HCT in FA patients, with particular emphasis on the timing and approach to HCT.     

Allogeneic hematopoietic cell transplantation for MDS: For whom,when and how?

Hematopoietic cell transplantation (HCT) is currently the only treatment with curative potential for patients with myelodysplastic syndrome (MDS). However, treatment-related mortality and relapse have remained major barriers to uniform success. Therefore, important questions remain to be answered, such as whom to transplant, when and how. With reduced intensity conditioning (RIC) regimens, patients in their 70s and patients with comorbid conditions have been transplanted successfully, although the relapse incidence with this approach tends to be increased in comparison to high intensity regimens. Success rates are higher in patients transplanted at an early stage of their disease. Encouraging is the fact, that results with unrelated donors who are HLA-matched by high resolution typing are comparable to those achieved with HLA genotypically identical siblings. The establishment of cord blood as a source of stem cells, and the recent success with HLA-haploidentical related donors will allow the offering of HCT to virtually all patients. Dependent upon disease stage and characteristics, some 25% to 75% of transplanted patients will be cured. While 20%–30% of patients experience chronic medical problems after HCT, 70% report a “good to excellent” quality of life. New studies must focus on further reducing GVHD for all patients and on overcoming high relapse rates in patients with high risk disease.     

Is leishmaniasis an “unusual suspect” of infection in allogeneic transplantation?

Leishmaniasis is a disease of the immunocompetent population, more often affecting infants and young children. However, the number of leishmaniasis cases associated with immunosuppression has increased over the last 20 years. The visceral form of the disease, visceral leishmaniasis (VL), is identified as an opportunistic infection in immunosuppressed individuals, occurring mainly after solid organ transplantation, especially in renal transplant recipients. Limited data are available about VL after hematopoietic stem cell transplantation (HSCT). We report the cases of 3 patients with late VL after allogeneic HSCT, and review the literature.     

Not out of the woods yet: “Diabetic neuropathy” or “neuropathy associated with diabetes”?

The most frequent diabetic complication, diabetic neuropathy, lacks accessible objective assessments. The concept and definition of diabetic neuropathy should be rethought to achieve the successful development of diagnostic and therapeutic methods.

Distal symmetric polyneuropathy is the most prevalent diabetic complication. The current editorial refers to this distal symmetric polyneuropathy as diabetic polyneuropathy (DPN). The biggest problem that diabetologists must be aware of is that the diagnosis and treatment of DPN are far from satisfactory for both patients and healthcare professionals. On PubMed, over the past 50 years, the number of clinical trials for nephropathy has increased, which has established accessible objective screening tools, serum creatinine and urinary albumin (Figure 1). Thereafter, the number of studies on retinopathy, in which various treatments for angiogenesis have been proposed, has dramatically increased. In contrast, the number of clinical trials on DPN has remained at approximately half of the other two complications. The reason for the lowest number of trials on the most frequent complications can be attributed to the lack of accessible objective assessments and stagnant development of new therapies.Open in a separate windowFigure 1The number of clinical trials for diabetic complications. The y‐axis represents the number of clinical trials per 5 years. The x‐axis represents the period of observation.There is no technical problem in establishing accessible objective assessments, but rather, we are in the final stage of determining the optimum solution. Composite indices of subjective symptoms, Achilles tendon reflex and vibration sensation using a tuning fork have been the major method of clinical diagnosis for DPN so far. However, it is difficult to detect neurodysfunction in the early stages of DPN using these low‐reproducibility indices.To address this problem in diagnosis, many testing devices or methods for evaluating peripheral nerve dysfunction or morphological abnormality have been proposed. Although the nerve conduction study (NCS) is classically the most reliable functional test, the lack of standardized interpretation of its results has been a barrier to carrying out multicenter clinical trials. In Japan, standardization has been attempted in interpreting the results of NCS, and as a result, it is widely used in medical institutions as Baba’s classification on the severity of DPN. ¹ Although this classification would be of great benefit to define the outcomes of clinical trials for DPN, it has not cleared the barrier of availability.However, the point‐of‐care NCS device, NC‐stat DPNCheck, which is designed to facilitate standardized electrode placement, is expected as a testing device that can eliminate this barrier. It has been verified in the past two decades that this device can partly replace the roles of conventional NCS. The high reproducibility in technical performance of this point‐of‐care device is superior to that of conventional NCS in which minor technical variations can yield inconsistent results. This device will provide accessible, objective and repetitive assessment of DPN, even in developing areas with limited medical resources. Various semiquantitative subjective tests other than this device have been proposed: Neuropad, NeuroQuick, Ipswich Touch Test, Vibratip and NerveCheck. These tests might also be used for diagnosis, along with DPNCheck. Additionally, among the tests for diabetic autonomic neuropathy, RR interval variability on the electrocardiogram is commonly available data. As the values of the variability have low reproducibility, it might be appropriate to use these data as an adjunct to the diagnosis of DPN, such as the use of urinary albumin in the diagnosis of diabetic nephropathy. To develop treatments for DPN, diagnostic criteria that are quantitative and objective, and can be easily applied in daily clinical practice should be established.Insufficient understanding of the mechanism is the most important barrier to developing new therapies for DPN. As various mechanisms have been proposed, most researchers report that the pathogenesis of DPN consists of multiple factors, and intervention on a single factor is not sufficient to prevent the development and progression of DPN. Based on this pathogenetic theory, the pathogenetic factors of DPN can be roughly divided into two: peripheral ischemia and metabolic changes associated with hyperglycemia. However, no individual pathogenetic hypothesis has been proven to be superior to other hypotheses. The lack of sufficient evidence for each hypothesis might be caused by insufficient therapeutic effectiveness of each intervention.We, researchers, should responsibly verify our unique hypothesis without being affected by research trends in academia. For example, researchers should not blindly flock to large currents, such as oxidative stress; rather, to understand the complex factors that regulate oxidative stress, we should carefully explore the cascade of unique molecules. Apart from the detailed studies that explore the pathology, we should also proceed with studies that compare the effectiveness of various suggested therapies. First, the impact of recent advances in glycemic control on the development and progression of DPN should be investigated. Thereafter, the additive effects of the existing approved drugs, α‐lipoic acid and aldose reductase inhibitor, should be evaluated.When carrying out a clinical trial, we should keep in mind using accessible objective assessments and to have a long‐term observation period. In these tests, as the symptoms and signs, which are often included as a primary end‐point due to the request by an examination authority in each country, impair objectivity and do not necessarily indicate an exacerbation of DPN stages, these symptoms and signs should not be used as primary end‐points. Accumulating experience through these trials of hypoglycemic therapies and the approved drugs will enable us to develop stronger strategies when planning clinical trials for new drugs.We now need to rethink the concept and definition of DPN to avoid future confusion in anticipation of the successful development of diagnostic and therapeutic methods for DPN. Although the most common clinical picture of diabetic polyneuropathy is distal symmetry, the current comprehensive classifications of diabetic neuropathy proposed by each country or organization include focal neuropathies. However, it is not guaranteed that these neuropathies with diverse clinical features have a common pathology. Rather, to promote accurate scientific verification, it would be better to consider that each individual neuropathy has a unique pathological mechanism. Therefore, is it appropriate to define diabetic neuropathy as a term that refers to DPN and tentatively call other neuropathies “neuropathy associated with diabetes” (Figure 2)? A comprehensive classification scheme for the diabetic neuropathies in the current position statement by the American Diabetes Association ² includes neuropathies that might not be directly caused by diabetes. Therefore, the term “neuropathy associated with diabetes” would be more accurate. By changing the disease name to neuropathy with diabetes, it becomes clearer that the pathophysiology of the diseases included here is diverse, and it is expected that a unique approach tailored to each neuropathy will be developed.Open in a separate windowFigure 2The classification of peripheral neuropathies in patients with diabetes. The schematic Venn diagram of the classification. Each circle represents an assumption of the similar etiology. CIDP, chronic inflammatory demyelinating polyneuropathy; MetS, metabolic syndrome.We scientists should not forget that the way of thinking among humans, including patients, is irrational. People do not feel the necessity to immediately address potentially progressive illnesses, such as diabetes and DPN, even if they understand that these illnesses greatly impair their career choices in life. As a result, many government agencies, researchers, clinicians and patients pretend not to see the diseases. Although necessity is the mother of invention, we have a responsibility to accurately diagnose and treat DPN before the patient becomes aware of it. We must now take action to improve diagnosis and treatment of DPN.     

Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome

Background

The role of reduced intensity conditioning allogeneic stem transplantation (RICalloSCT) in the management of patients with Hodgkin’s lymphoma remains controversial.

Design and Methods

To further define its role we have conducted a retrospective analysis of 285 patients with HL who underwent a RICalloSCT in order to identify prognostic factors that predict outcome. Eighty percent of patients had undergone a prior autologous stem cell transplantation and 25% had refractory disease at transplant.

Results

Non-relapse mortality was associated with chemorefractory disease, poor performance status, age >45 and transplantation before 2002. For patients with no risk factors the 3-year non-relapse mortality rate was 12.5% compared to 46.2% for patients with 2 or more risk factors. The use of an unrelated donor had no adverse effect on the non-relapse mortality. Acute graft versus host disease (aGVHD) grades II–IV developed in 30% and chronic GVHD in 42%. The development of cGVHD was associated with a lower relapse rate. The disease progression rate at one and five years was 41% and 58.7% respectively and was associated with chemorefractory disease and extent of prior therapy. Donor lymphocyte infusions were administered to 64 patients for active disease of whom 32% showed a clinical response. Eight out of 18 patients receiving donor lymphocyte infusions alone had clinical responses. Progression-free and overall survival were both associated with performance status and disease status at transplant. Patients with neither risk factor had a 3-year PFS and overall survival of 42% and 56% respectively compared to 8% and 25% for patients with one or more risk factors. Relapse within six months of a prior autologous transplant was associated with a higher relapse rate and a lower progression-free.

Conclusions

This analysis identifies important clinical parameters that may be useful in predicting the outcome of RICaIICalloSCT in Hodgkin’s lymphoma.     

Dose intensity for induction in acute myeloid leukemia: what,when, and for whom?

Intensive chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML) for decades. However, an increase in novel targeted agents, which has been brought about in part by a deeper understanding of the genetic makeup of AML, has led to remission- inducing regimens that do not require traditional cytotoxic agents. Combinations of a hypomethylating agent (HMA) and venetoclax have doubled the chance of remission for patients considered unfit for induction chemotherapy who would have traditionally been offered singleagent HMA. In fact, this regimen may rival the complete remission rate achieved with induction chemotherapy for certain populations such as the very elderly and those with secondary AML, but equivalency has yet to be established. Further advances include the addition of gemtuzumab ozogamicin and FLT3 inhibitors to induction chemotherapy, which improves survival for patients with core-binding factor and FLT3-mutated AML, respectively. Still, much work is needed to improve the outcomes of the highest-risk subgroups: frail patients and those with high-risk cytogenetics and/or TP53 mutations. Promisingly, the landscape of AML therapy is shifting dramatically and no longer is intensity, when feasible, always the best answer for AML.     

Influenza and Pneumocystis jirovecii pneumonia in an allogeneic hematopoietic stem cell transplantation recipient: Coinfection or superinfection?

Influenza infection and Pneumocystis jirovecii pneumonia (PJP) in hematopoietic stem cell transplant (HSCT) patients are well characterized; however, no dual infections have been reported in this patient population and little evidence of mechanisms of interaction between the two infections exists. We present a 53‐year‐old male allogeneic HSCT patient on immunosuppressive therapy for the treatment of graft versus host disease initially diagnosed with influenza A H3 and later PJP. Despite the development of acute respiratory distress syndrome, the patient was successfully treated with appropriate antimicrobial therapy and aggressive supportive care. This case demonstrates the necessity of maintaining a high index of suspicion for fungal (including PJP) coinfection or superinfection in the setting of worsening influenza infection.     

Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation

To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 μCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning.     

Novel therapies vs hematopoietic cell transplantation in myelofibrosis: who,when, how?

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Stem cell transplantation for mantle cell lymphoma: if, when and how?

Although the prognosis for mantle cell lymphoma (MCL) patients has improved in recent years, the outlook for those with advanced or recurrent disease remains poor. High-dose chemotherapy and autografting performed early in responding patients appears to be a method to extend progression-free survival (PFS) and overall survival (OS). The use of monoclonal antibody therapy added into the initial therapy and in the peritransplant period may improve on these results. Myeloablative allogeneic transplant appears to be a modality capable of providing curative therapy, but is plagued by a high treatment-related mortality, especially in older patients. Reduced-intensity conditioning allografting have fewer problems associated with the initial phase of transplant and hence may be preferred for those patients for whom an allograft is considered but have comorbid conditions or age issues that preclude a full allograft. Long-term results are lacking and the side effects associated with chronic GVHD may be as significant and debilitating. Trials designed to look at newly diagnosed patients with MCL examining the outcomes after planned autologous and allogeneic transplant as part of the initial management are needed to confirm the role of these various modalities in the overall therapy of this poor-outcome lymphoma.