Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies.

This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.

How I treat pain in hematologic malignancies safely with opioid therapy.

The field of malignant hematology has experienced extraordinary advancements with survival rates doubling for many disorders. As a result, many life-threatening conditions have since evolved into chronic medical ailments. Paralleling these advancements have been increasing rates of complex hematologic pain syndromes, present in up to 60% of patients with malignancy who are receiving active treatment and up to 33% of patients during survivorship. Opioids remain the practice cornerstone to managing malignancy-associated pain. Prevention and management of opioid-related complications have received significant national attention over the past decade, and emerging data suggest that patients with cancer are at equal if not higher risk of opioid-related complications when compared with patients without malignancy. Numerous tools and procedural practice guides are available to help facilitate safe prescribing. The recent development of cancer-specific resources directing algorithmic use of validated pain screening tools, prescription drug monitoring programs, urine drug screens, opioid use disorder risk screening instruments, and controlled substance agreements have further strengthened the framework for safe prescribing. This article, which integrates federal and organizational guidelines with known risk factors for cancer patients, offers a case-based discussion for reviewing safe opioid prescribing practices in the hematology setting.

Copper-associated hepatitis in a patient with chronic myeloid leukemia following hematopoietic stem cell transplantation: A case report.

RATIONALE: We report a complicated case of cholestatic hepatitis with suspected autoimmune hemolytic anemia (AIHA) and copper toxicity syndrome after HSCT and donor lymphocyte infusion (DLI). PATIENT CONCERNS: A 19-year-1-month-old girl presented with a history of CML. She underwent matched unrelated donor HSCT and donor lymphocyte infusion subsequently. Three months later, yellowish discoloration of the skin was found, which was accompanied by progressive itchy skin, easy fatigability, insomnia, and dark urine output. After admission, liver function disorders were observed. INTERVENTION: Methylprednisolone was administered for suspected hepatic GVHD. Although abdominal sonography revealed no evidence of biliary tract obstruction and the viral hepatitis survey disclosed unremarkable findings; silymarin and ursodeoxycholic acid were administered to preserve the liver function. In addition, rituximab was prescribed for suspected AIHA. Because hyperbilirubinemia was progressive, mycophenolate and high-dose intravenous immunoglobulin were accordingly administered. As drug-induced liver injury cannot be excluded, all potential unconfirmed causes of drug-related hepatoxicity were discontinued. DIAGNOSIS: In this case, the patient's history of shrimps and chocolate consumption led us to strongly suspect cholestatic hepatitis associated with copper toxicity syndrome. High 24-hour urine copper excretion and low serum zinc levels were also confirmed. Accordingly, D-penicillamine and zinc gluconate were administered. OUTCOMES: She succumbed to progressive hepatic failure and eventual multisystem organ failure 14 months after HSCT. No autopsy was performed. LESSONS: This report described the combined effects of hepatic GVHD, AIHA, drugs, and copper toxicity on liver damage, and demonstrated the potential diagnostic challenges and treatment dilemmas associated with this disease.

Elevated Cardiovascular Disease Risk in Patients With Chronic Myelogenous Leukemia Seen in Community-based Oncology Practices in the United States.

INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend that comorbidities, including cardiovascular disease (CVD), be considered when selecting tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia (CML). We report here the prevalence of CVD and its risk factors in patients with CML treated by community-based United States (US) oncologists. PATIENTS AND METHODS: Adult patients with a confirmed diagnosis of CML and ≥ 1 encounter after the first date of CML diagnosis in an electronic medical record database between January 1, 2005 and October 31, 2014 were enrolled. CVD conditions/risk factors were assessed at baseline and during the 5-year follow-up period using International Classification of Diseases, 9th Revision, Clinical Modification diagnoses codes and information from physician progress notes. One-year prevalence estimates were age- and gender-standardized for comparison to annual rates in the US population. RESULTS: A total of 1639 patients were included. At 5-year follow-up, the prevalence of CVD conditions and CVD risk factors was 33.0% and 77.7%, respectively. Compared with the general US adult population, the standardized prevalence rates at 1 year in patients with CML were significantly higher by factors of 1.3 to 3.5 times for CVD conditions, and 20% to 40% significantly higher for hypertension, diabetes, and obesity (P < .001). The prevalence of cardiovascular risk factors was not significantly higher in patients residing in the US Stroke Belt. CONCLUSION: The increased risk of CVD observed in this real-world analysis of patients with CML underscores the importance of current National Comprehensive Cancer Network recommendations to consider cardiovascular risk when selecting tyrosine kinase inhibitors.

[Efficacy of levocarnitine for tyrosine kinase inhibitor-induced painful muscle cramps in patients with chronic myelogenous leukemia].

Muscle cramps are side effects commonly associated with tyrosine kinase inhibitor (TKI) treatment. Patients suffering from muscle cramps are treated with various medications such as calcium, magnesium and vitamin supplements, but these therapies are often ineffective. We report two patients with chronic myelogenous leukemia who developed muscle cramps caused by TKI. These patients were treated successfully with levocarnitine. Both of our cases revealed the beneficial effects of levocarnitine treatment on TKI-induced muscle cramps.

Diseases at the crossroads: chronic myelogenous leukemia and tuberculosis.

Chronic myelogenous leukemia (CML) and tuberculosis (TB) are diseases with effective available therapy. Treating patients who are afflicted simultaneously with both of these conditions is challenging due to significant drug interactions and the requirement of strict adherence to the multi-agent treatment regimen. Here, we report a case of peritoneal tuberculosis which was successfully treated with a non-rifampin based regimen in tandem with ongoing administration of a tyrosine kinase inhibitor, dasatinib, for CML. We discuss treatment challenges and the strategy on how to circumvent them. As prevalence of CML increases worldwide, patients with concomitant CML and TB will be seen more often by physicians in all continents, and development of guidelines on simultaneous management of these conditions is imperative.

Management options for refractory chronic myeloid leukemia: considerations for the elderly.

Despite the excellent results obtained with standard-dose imatinib as first-line therapy for chronic myeloid leukemia in the chronic phase, one third of patients do not achieve an optimal response and require alternative therapies due to the emergence of drug resistance. Studies of resistance mechanisms, first tested in vitro and then in vivo, have driven the development of second-generation tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib. These agents have been proven effective in a large number of patients resistant to imatinib and are also effective in older patients. The use of second-generation TKIs in first-line treatment has increased the rate of cytogenetic and molecular responses and reduced the number of patients experiencing disease progression. In this review, we detail the various mechanisms of resistance and management options for refractory patients, in particular in older patients. No differences in terms of efficacy were reported in this subset of patients when treated with nilotinib or dasatinib after imatinib resistance. Results of trials that tested second-generation TKIs as first-line treatment showed similar results in older and younger patients.

Substance use and survival after treatment for chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS).

BACKGROUND: Patients' substance use problems are a particularly understudied aspect of psychosocial variables in cancer treatment. OBJECTIVES: The specific hypothesis tested was that lifetime substance use disorders increased the risk of adverse outcome, in the context of other psychosocial and clinical characteristics demonstrated in other studies to have an impact on treatment outcome. METHOD: Prospective cohort study of 106 adults with chronic myelogenous leukemia or primary myelodysplastic syndrome. None satisfied criteria for current substance abuse or dependence, but the lifetime rates of substance use disorders in this sample were 28% for alcohol, 12% for cannabis, and 9% for cocaine. RESULTS: Participants received treatment as directed by their physicians, and were followed until death or the end of the study (median 1.5 years). Twenty-eight died. Multivariate survival analysis identified three predictors of outcome: lifetime cocaine use, associated with a six-fold increased risk of death (p = .04), and two protective variables, baseline hemoglobin (p = .002) and estimated intelligence quotient (IQ) (p = .04). CONCLUSION: The results of this study highlight the potential significance of substance use disorders, and lifetime cocaine diagnoses in particular, on treatment outcome for people with chronic myelogenous leukemia or myelodysplastic syndrome. Whereas neither lifetime alcohol nor cannabis use were associated with survival on either the univariate or multivariate models of survival, lifetime cocaine diagnoses were associated with significant six-fold increased risk of death (p = .04).

[Ganciclovir-resistant cytomegalovirus infection: 2 cases with different clinical impact]. / Ganciclovir-resistente Zytomegalievirus-Infektion: 2 Fälle mit unterschiedlicher klinischer Bedeutung.

Swiss cases of cytomegalovirus (CMV) resistance to antiviral drugs have not been reported to date. We describe both a documented and a presumed case of ganciclovir-resistant CMV infection. A bone marrow transplant recipient with an episode of CMV viremia and antigenemia underwent broncho-alveolar lavage from which a CMV strain was isolated. The sensitivity of this strain to ganciclovir and foscarnet was tested in a plaque reduction assay, which was performed in 6 different fibroblast lines. The inhibitory drug concentration which reduced viral plaque formation by 50% (IC50) was a median of 12.7 microM (range 6.1-29.6) for ganciclovir (resistance defined as IC50 > 6 microM), which documented the presence of CMV resistance to ganciclovir. The strain was sensitive to foscarnet. This ganciclovir-resistant CMV strain had no clinical impact, although the patient was treated with ganciclovir. A second patient had Aids and subsequently developed CMV retinitis which was treated with intravenous ganciclovir for 3 weeks, followed by longterm oral ganciclovir therapy. Approximately 4 1/2 months after initiation of antiviral therapy the patient developed fatal CMV multi-organ disease while on continued oral ganciclovir treatment, which suggested the occurrence of CMV resistance to this agent. CMV organ disease was documented at autopsy by histology and immunochemistry, but virus was not cultured. The different outcomes in these two patients suggest that the type of underlying immunodeficiency may be a decisive factor for the clinical relevance of drug-resistant CMV infection.

Chronic myelogenous leukemia in a 16-yr-old.

OBJECTIVE: To present an unusual case of chronic myelogenous leukemia (CML) in an adolescent with a complaint of leg pain. Clinical presentation is highlighted and a brief review of the childhood leukemias and common clinical features are outlined. CLINICAL FEATURES: A 16-yr-old black male was seen after suffering from leg and knee pains for 7 months. Exquisite tibial pain, normal radiographs and an abnormal CBC led to the diagnosis of leukemia. Subsequent referral for bone marrow examination confirmed the final diagnosis of chronic myelogenous leukemia. INTERVENTION AND OUTCOME: The patient was referred to a pediatric hematologist-oncologist for medical management of his condition. He is currently receiving chemotherapy and the search for a suitable donor for bone marrow transplant is in progress. CONCLUSION: This case demonstrates the importance of considering one of the more common pediatric malignancies, such as leukemia, in the differential diagnosis of children with musculoskeletal complaints. Chronic myelogenous leukemia accounts for only 3-5% of cases of childhood onset. Its rare incidence in childhood constitutes the basis for this case report.

Central catheter infection by Trichosporon beigelii after autologous blood stem cell transplantation. A case report and review of the literature.

A case of localized Trichosporon beigelii infection is reported in a 40-year-old woman with Ph+ chronic granulocyte leukemia who underwent autologous blood stem cell transplantation. On day +14 after autograft, while severely neutropenic, she developed a local infection involving the soft tissues surrounding the central venous catheter (CVC) point of entry into the subclavian vein. Trichosporon beigelii was isolated from culture of the CVC tip; resolution occurred after removal of the CVC, neutrophil recovery and antifungal treatment with amphotericin B and 5-fluorocytosine. To our knowledge this is the first case of CVC localized infection from Trichosporon beigelii after transplantation.

A case of combined primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.

A rare case of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia is described in a 49-year-old Japanese diabetic woman. Primary biliary cirrhosis was diagnosed by characteristic liver histology and positive serum mitochondrial antibody test. Ulcerative colitis was diagnosed by typical findings of barium enema and colonoscopy, negative fecal test for pathogens and compatible rectal histology. Chronic myelocytic leukemia was determined by representative hematologic findings and positive result for Ph1 chromosome. This is the first case with combination of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.

One-shot high-dose pamidronate disodium (APD): effective, simple treatment for hypercalcaemia in haematological malignancy.

Fifteen patients with haematological malignancy and hypercalcaemia (mean +/- SEM calcium 3.44 +/- 0.14 mmol/l) received pamidronate (1 mg/kg) by infusion on 17 occasions (two patients were retreated 2 and 6 months after the first dose). After 4 days the plasma calcium had fallen to 2.84 +/- 0.14 mmol/l (P less than 0.001; n = 17), and in 10/17 episodes was less than 2.6 mmol/l. The mean fall was 0.61 mmol/l (95% confidence intervals 0.49-0.72 mmol/l). By 7 days a further decrease to 2.53 +/- 0.10 mmol/l had occurred, continuing to 2.38 +/- 0.11 mmol/l after 14 days. Plasma phosphate fell from 1.18 +/- 0.16 to 0.74 +/- 0.07 mmol/l at 7 days (P less than 0.001; n = 12). In 9 of the 17 episodes plasma creatinine initially exceeded 120 mumol/l (four of these greater than 300 mumol/l). This did not impair the response to pamidronate and there was no significant change in plasma creatinine following treatment. A single large dose of pamidronate was a simple, well-tolerated and very reliable treatment for hypercalcaemia complicating haematological malignancy, irrespective of renal function.