Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Efficacy and safety of combination therapies vs monotherapy of hypomethylating agents in accelerated or blast phase of Philadelphia negative myeloproliferative neoplasms: a systematic review and meta-analysis.

BACKGROUND: There is a lack of evidence regarding whether combination therapy of hypomethylating agents (HMAs) has better outcomes than HMA monotherapy in patients with Philadelphia chromosome-negative accelerated or blast phase myeloproliferative neoplasms (MPN-AP/BP). MATERIALS AND METHODS: Pubmed, Embase, Web of Science and Cochrane library databases were searched for studies from inception of each database until 31 December 2021. Data extraction and synthesis were conducted following the PRISMA reporting guideline. RESULTS: It was found that HMAs plus venetoclax therapy yielded a higher CR/CRi rate than HMAs alone [36% vs 19%, p = .0204] and a higher CR rate than HMAs plus ruxolitinib [22% vs 8%, p = .0313]. HMAs plus ruxolitinib combination showed a higher ORR than HMA monotherapy [45% vs 30%, p = .0395], but there was no improvement in CR/CRi. The one-year and two-year OS rate for patients treated with HMAs plus venetoclx/ruxolitinib demonstrated a trend towards prolonged survival than HMAs alone [HMAs plus venetoclax: 24% vs 11%, p = .1295 and 12% vs 3%, p = .2357; HMAs plus ruxolitinib: 25% vs 11%, p = .0774 and 33% vs 3%, p = .051]. CONCLUSION: It was confirmed that HMA in combination with venetoclax is an effective and well-tolerated option in MPN-AP/BP patients in pre- as well as post-haematopoietic stem cell transplantation settings. HMA plus ruxolitinib therapy was revealed to be effective in patients with MPN-AP.Key MessagesCombination therapy with HMAs and venetoclax/ruxolitinib was associated with improved outcomes than HMAs alone in MPN-AP/BP patients.Further large-scale randomized controlled trials are needed to confirm regarding to the optimal treatment for this patient population.

Leukemic arthritis and severe hypercalcemia in a man with chronic myeloid leukemia: a case report and review of the literature.

BACKGROUND: Patients with chronic myeloid leukemia typically present with high white blood cell counts revealed during annual checkups. Leukemic arthritis and hypercalcemia are rare manifestations in patients with chronic myeloid leukemia. CASE PRESENTATION: A 35-year-old Thai man who had been diagnosed with chronic myeloid leukemia in the chronic phase developed blast crisis while he was receiving ongoing treatment with imatinib at 400 mg/day. Initially, he presented with oligoarthritis in both knees and ankles. A bone scintigraphy showed a prominent bony uptake, with a symmetrical, increased uptake in many bone areas. Induction therapy with a 7 + 3 induction regimen was prescribed in conjunction with 600 mg of imatinib once daily before switching to 140 mg of dasatinib. He subsequently developed severe hypercalcemia (total serum calcium of 17.8 mg/dL), with generalized osteolytic lesions detected on a bone survey. His serum vitamin D level was 50.64 ng/mL, while the serum parathyroid hormone level was 9.82 pg/mL. Despite the administration of an aggressive intravenously administered hydration, intravenously administered calcitonin, and 600 mg/day of imatinib, the severe hypercalcemia was refractory. We therefore decided to prescribe 20 mg/day of intravenously administered dexamethasone; fortunately, his serum calcium level decreased dramatically to normal range within a few days. CONCLUSIONS: Although leukemic arthritis and severe hypercalcemia are extraordinary presentations in patients with chronic myeloid leukemia, the advanced phase of the disease might bring on these symptoms. Apart from parathyroid hormone-related protein-related hypercalcemia, vitamin D is a mechanism of humoral-mediated hypercalcemia.

Fatal stimulation of acute myeloid leukemia blasts by pegfilgrastim.

UNLABELLED: We herein report the case of a male patient with acute myeloid leukemia with fatal outcome attributable to pharmacokinetics of pegfilgrastim. CASE REPORT: An unexplained blast proliferation in a patient with acute myeloid leukemia following cytotoxic induction chemotherapy was investigated in depth. Myeloblast hyperstimulation was likely related to pegfilgrastim, the long half-life of which extended the duration of side-effects, resulting in massive and rapidly fatal leukemia cell proliferation. CONCLUSION: Pegfilgrastim can cause unexpected deleterious effects in acute myeloid leukemia. We, thus, recommend administering drugs with a shorter half-life, such as filgrastim or lenograstim, to reduce infection incidence in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.

Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML.

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.

Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate.

Sudden blastic transformation (SBT) has been reported in 0.5% to 2.5% of patients treated with interferon-alpha (IFN-alpha) during the first 3 years of therapy. Imatinib is now standard therapy for patients with chronic myeloid leukemia in chronic phase. We investigated the occurrence of SBT among patients treated with imatinib. Among 541 patients treated with imatinib in chronic phase, 23 developed blast phase, which was of sudden onset (ie, occurring in patients previously in complete cytogenetic remission) in 4 patients (17%; 0.7% of the total), 2 lymphoid and 2 myeloid. Patients with SBT were found to have low-risk features more often at the time of presentation and had achieved optimal response with imatinib. Three of the 4 patients underwent allogeneic stem cell transplantation and achieved a molecular remission. SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory.

Pathobiology of lymphoid and myeloid blast crisis and management issues.

Despite recent improvements in the treatment of early-stage disease, the blastic phase of chronic myeloid leukemia (CML) remains a therapeutic challenge. For imatinib-naïve patients, imatinib provided encouraging hematologic and cytogenetic benefits; however, the vast majority of CML blast crisis cases today arise in patients already on imatinib-based therapy. Clonal evolution and duplication of the Philadelphia chromosome continue to be associated with blastic phase transformation, but recent studies have identified BCR/ABL kinase domain mutations in 30%-40% of blast crisis patients. This implies that BCR-ABL-targeted therapy might have influenced the molecular road map to blastic transformation. In this review, we will examine the effect of imatinib on primitive CML progenitors and how this might influence the pathophysiology of blast crisis. A rational framework for deciding how best to integrate stem cell transplantation, traditional chemotherapy, imatinib, and other BCR-ABL kinase inhibitors in the care of blast crisis patients will also be discussed.

Subdural hematomas during CML therapy with imatinib mesylate.

Seven of one hundred twenty-one patients with chronic myeloid leukemia (CML) treated with imatinib mesylate developed subdural hematomas. All had advanced disease and were treated initially at a dose of 600 mg per day. Three patients had thrombocytopenia (platelet < 10 x 10(9)/l), one had leukocytosis (white blood cell count > 150 x 10(9)/l) and three had neither around the time of diagnosis of the subdural hematomas. Four patients required surgical evacuation. One patient, in blast crisis, died as a consequence of the subdural hematoma. Three patients survived but died of progressive CML. The remaining three patients having recommenced imatinib, are alive and well, and one has achieved a major cytogenetic response. Subdural hematomas must be considered even in mildly symptomatic patients receiving imatinib regardless of their peripheral blood counts. Patients who survive can be cautiously restarted on imatinib. Further studies are required to study the potential relationship between imatinib mesylate and subdural hematomas.

Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia.

Imatinib mesylate, a specific inhibitor of the BCR-ABL tyrosine kinase, has been very effective in the treatment of chronic myeloid leukemia (CML) in chronic phase with high rates of hematological and cytogenetic remissions. Resistance to therapy can develop and transformation to blast crisis may occur, particularly in patients without a cytogenetic response. We report a case of a patient with CML treated in chronic phase who developed blast crisis; withdrawal of imatinib mesylate resulted in spontaneous reversion to chronic phase.

Lymphoid blast crisis during interferon-alpha therapy in a patient with chronic myelogenous leukemia in myeloid blast crisis.

A 47-year-old woman was admitted to the hospital on March 13, 1998, because of general malaise and fever. It was determined that she had chronic myelogenous leukemia (CML) in myeloid blast crisis. Hydroxyurea was started initially, and the blasts completely disappeared from peripheral blood on day 9 of therapy. Interferon (IFN)-alpha was subsequently started, but lymphoblasts newly appeared on day 13 of administration. Treatment with adriamycin, vincristine, and prednisolone (AdVP) was immediately started, which rapidly reduced the lymphoblasts. However, the myeloblasts again began to gradually increase. Subsequent examinations showed the combined presence of myeloblasts and lymphoblasts in the marrow and peripheral blood. The ratio between myeloblasts and lymphoblasts depended on the treatment (IFN-alpha or AdVP). The patient died from respiratory failure on November 16, 1998. This patient may have had an underlying bipotential blastic clone that evolved differently in response to IFN-alpha or AdVP. In some CML patients, IFN-alpha may induce lymphoid blast crisis.

Influencia de las condiciones de cultivo de placenta humana sobre la producción de medios condicionados placentarios / Influence of culture conditions on the production of human placent conditioned medium

En este trabajo se propone una técnica alternativa para la obtención de medios condicionados derivados de placenta humana. Se cultivaron homogenatos placentarios en Mc Coy's 5A suplementado con suero fetla bovino al 5 por ciento y 25mM de HEPES a 37oC. Luego de seis días, los cultivos fueron sacrificados, verificándose la esterilidad y la viabilidad celular. El sobrenadante fue centrifugado a 22.000 g 30 min a 4oC y esterilizado por filtración (0,22 um), denominándolo Medio Condicionado de Placenta Humana (MCPH). Se probó la actividad de los extractos, así obtenidos, en cultivos de linfocitos periféricos de mujeres con tres hijos, con la adición de MCPH al 5 por ciento ,10 por ciento y 20 por ciento y se determinó el índice de Transformación Blástica Linfocitaria (ITBL). La máxima estimulación se observó en los cultivos linfocitarios que contenían MCPH al 10 por ciento , siendo estos valores más uniformes que losa producidos con MCPH al 10 por ciento obtenidos por otra técnica. en conclusión, con esta metodología es posible obtener medios condicionados placentarios con una actividad estimulante más uniforme, independientemente de la placenta de la cual provengan

Influencia de las condiciones de cultivo de placenta humana sobre la producción de medios condicionados placentarios / Influence of culture conditions on the production of human placent conditioned medium

En este trabajo se propone una técnica alternativa para la obtención de medios condicionados derivados de placenta humana. Se cultivaron homogenatos placentarios en Mc Coys 5A suplementado con suero fetla bovino al 5 por ciento y 25mM de HEPES a 37oC. Luego de seis días, los cultivos fueron sacrificados, verificándose la esterilidad y la viabilidad celular. El sobrenadante fue centrifugado a 22.000 g 30 min a 4oC y esterilizado por filtración (0,22 um), denominándolo Medio Condicionado de Placenta Humana (MCPH). Se probó la actividad de los extractos, así obtenidos, en cultivos de linfocitos periféricos de mujeres con tres hijos, con la adición de MCPH al 5 por ciento ,10 por ciento y 20 por ciento y se determinó el índice de Transformación Blástica Linfocitaria (ITBL). La máxima estimulación se observó en los cultivos linfocitarios que contenían MCPH al 10 por ciento , siendo estos valores más uniformes que losa producidos con MCPH al 10 por ciento obtenidos por otra técnica. en conclusión, con esta metodología es posible obtener medios condicionados placentarios con una actividad estimulante más uniforme, independientemente de la placenta de la cual provengan(AU)

[Lymphocyte response of blast transformation and some parameters of hormonal status in patients with type II diabetes mellitus]. / Reaktsiia blasttransformatsii limfotsitov i nekotorye pokazateli gormonal'nogo statusa u bol'nykh sakharnym diabetom II tipa.

Tests were conducted to analyze a blastogenic response of lymphocytes to phytohemagglutinin (PHA) in autoserum and bovine serum and the hormone level of blood of the second-type diabetes patients. The results indicate that there is a positive correlation between a blastogenic response to PHA in the autoserum medium on the one hand and the T4 level and insulin on the other hand. There is a negative correlation between the first factor and the glycemic index and the duration of disease. There is no correlation between a mitogenic response and the examinees' age. The blood insulin level also correlates with a mitogenic response of lymphocytes in bovine serum. The examination of patients in the compensation stage suggests a negative correlation between a cortisol level and the stimulation index logarithm of a mitogenic response in bovine serum. This correlation did not exist in cases of decompensated diabetes.