Leukemia, Myelodysplasia, Transplantation

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.

The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.

Sharon Worcester/Frontline Medical News

“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.

The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.

“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.

In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.

Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.

Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.

Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.

The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.

This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.

[email protected]

SOURCE: Rutella S et al. ASCO-SITC Abstract 50

SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.

The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.

Sharon Worcester/Frontline Medical News

“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.

The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.

“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.

In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.

Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.

Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.

Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.

The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.

This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.

[email protected]

SOURCE: Rutella S et al. ASCO-SITC Abstract 50

SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.

The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.

Sharon Worcester/Frontline Medical News

“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.

The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.

“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.

In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.

Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.

Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.

Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.

The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.

This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.

[email protected]

SOURCE: Rutella S et al. ASCO-SITC Abstract 50

Photo by Rhoda Baer

Socioeconomic deprivation may decrease survival in adults with acute lymphoblastic leukemia (ALL), according to research published in BMC Cancer.

Researchers found that ALL patients living in more deprived areas of England had a 16% to 21% greater risk of dying than patients living in the least deprived areas.

The researchers also observed a 33% higher risk of mortality in patients who were treated at hospitals that manage few ALL patients.

“The findings are likely to have significant implications for the organization of NHS [National Health Service] services for the treatment of adults with this rare but serious condition,” said study author Ravi Maheswaran, MD, of the University of Sheffield in Sheffield, UK.

To conduct this study, Dr Maheswaran and Nick Morley, MBBS, of Royal Hallamshire Hospital in Sheffield, analyzed anonymized NHS data on hospital admissions.

The researchers identified 2921 adults (age 18 and older) who were diagnosed with ALL from 2001 to 2012 and assessed follow-up data on survival rates up to 2013.

There were 1870 deaths during follow-up, and the 5-year survival rate was 32%.

As expected, survival decreased with age but increased over time. The mortality hazard ratio (HR) was 1.38 for patients ages 30 to 39, 3.72 for patients ages 60 to 69, and 9.02 for patients age 80 and older.

The HR was 0.98 for patients diagnosed from 2005 to 2008 and 0.70 for patients diagnosed from 2009 to 2012, compared to 1.00 for patients diagnosed from 2001 to 2004.

Patients living in areas of socioeconomic deprivation had a greater risk of death, but it did not seem to matter whether the patients lived in rural or urban areas.

The mortality HR was 1.16 for patients living in the most deprived areas and 1.21 for patients in intermediate areas (with the least deprived areas as the reference, 1.00). The HR was 1.00 for both rural and urban areas.

The risk of death was higher for patients treated at hospitals with low volumes of adults with ALL. The mortality HR was 1.33 for low-volume hospitals, which were defined as hospitals with 15 or fewer ALL patients admitted over a 3-year time period for which data were available.

“These results, although concerning, are from a single study, and further work is needed to confirm our findings,” Dr Maheswaran said.

“If the association between high deprivation and poorer survival is confirmed, more investigation will be needed to understand why adults with this type of leukemia living in deprived areas have poorer survival and what can be done to address this inequality.”

“Confirmation that hospitals treating few patients with this rare condition have worse outcomes would mean that the NHS should seriously consider if treatment services for adults with acute lymphoblastic leukemia should mainly be provided by specialist centers in order to improve survival.”

Photo by Rhoda Baer

Socioeconomic deprivation may decrease survival in adults with acute lymphoblastic leukemia (ALL), according to research published in BMC Cancer.

Researchers found that ALL patients living in more deprived areas of England had a 16% to 21% greater risk of dying than patients living in the least deprived areas.

The researchers also observed a 33% higher risk of mortality in patients who were treated at hospitals that manage few ALL patients.

“The findings are likely to have significant implications for the organization of NHS [National Health Service] services for the treatment of adults with this rare but serious condition,” said study author Ravi Maheswaran, MD, of the University of Sheffield in Sheffield, UK.

To conduct this study, Dr Maheswaran and Nick Morley, MBBS, of Royal Hallamshire Hospital in Sheffield, analyzed anonymized NHS data on hospital admissions.

The researchers identified 2921 adults (age 18 and older) who were diagnosed with ALL from 2001 to 2012 and assessed follow-up data on survival rates up to 2013.

There were 1870 deaths during follow-up, and the 5-year survival rate was 32%.

As expected, survival decreased with age but increased over time. The mortality hazard ratio (HR) was 1.38 for patients ages 30 to 39, 3.72 for patients ages 60 to 69, and 9.02 for patients age 80 and older.

The HR was 0.98 for patients diagnosed from 2005 to 2008 and 0.70 for patients diagnosed from 2009 to 2012, compared to 1.00 for patients diagnosed from 2001 to 2004.

Patients living in areas of socioeconomic deprivation had a greater risk of death, but it did not seem to matter whether the patients lived in rural or urban areas.

The mortality HR was 1.16 for patients living in the most deprived areas and 1.21 for patients in intermediate areas (with the least deprived areas as the reference, 1.00). The HR was 1.00 for both rural and urban areas.

The risk of death was higher for patients treated at hospitals with low volumes of adults with ALL. The mortality HR was 1.33 for low-volume hospitals, which were defined as hospitals with 15 or fewer ALL patients admitted over a 3-year time period for which data were available.

“These results, although concerning, are from a single study, and further work is needed to confirm our findings,” Dr Maheswaran said.

“If the association between high deprivation and poorer survival is confirmed, more investigation will be needed to understand why adults with this type of leukemia living in deprived areas have poorer survival and what can be done to address this inequality.”

“Confirmation that hospitals treating few patients with this rare condition have worse outcomes would mean that the NHS should seriously consider if treatment services for adults with acute lymphoblastic leukemia should mainly be provided by specialist centers in order to improve survival.”

Photo by Rhoda Baer

Socioeconomic deprivation may decrease survival in adults with acute lymphoblastic leukemia (ALL), according to research published in BMC Cancer.

Researchers found that ALL patients living in more deprived areas of England had a 16% to 21% greater risk of dying than patients living in the least deprived areas.

The researchers also observed a 33% higher risk of mortality in patients who were treated at hospitals that manage few ALL patients.

“The findings are likely to have significant implications for the organization of NHS [National Health Service] services for the treatment of adults with this rare but serious condition,” said study author Ravi Maheswaran, MD, of the University of Sheffield in Sheffield, UK.

To conduct this study, Dr Maheswaran and Nick Morley, MBBS, of Royal Hallamshire Hospital in Sheffield, analyzed anonymized NHS data on hospital admissions.

The researchers identified 2921 adults (age 18 and older) who were diagnosed with ALL from 2001 to 2012 and assessed follow-up data on survival rates up to 2013.

There were 1870 deaths during follow-up, and the 5-year survival rate was 32%.

As expected, survival decreased with age but increased over time. The mortality hazard ratio (HR) was 1.38 for patients ages 30 to 39, 3.72 for patients ages 60 to 69, and 9.02 for patients age 80 and older.

The HR was 0.98 for patients diagnosed from 2005 to 2008 and 0.70 for patients diagnosed from 2009 to 2012, compared to 1.00 for patients diagnosed from 2001 to 2004.

Patients living in areas of socioeconomic deprivation had a greater risk of death, but it did not seem to matter whether the patients lived in rural or urban areas.

The mortality HR was 1.16 for patients living in the most deprived areas and 1.21 for patients in intermediate areas (with the least deprived areas as the reference, 1.00). The HR was 1.00 for both rural and urban areas.

The risk of death was higher for patients treated at hospitals with low volumes of adults with ALL. The mortality HR was 1.33 for low-volume hospitals, which were defined as hospitals with 15 or fewer ALL patients admitted over a 3-year time period for which data were available.

“These results, although concerning, are from a single study, and further work is needed to confirm our findings,” Dr Maheswaran said.

“If the association between high deprivation and poorer survival is confirmed, more investigation will be needed to understand why adults with this type of leukemia living in deprived areas have poorer survival and what can be done to address this inequality.”

“Confirmation that hospitals treating few patients with this rare condition have worse outcomes would mean that the NHS should seriously consider if treatment services for adults with acute lymphoblastic leukemia should mainly be provided by specialist centers in order to improve survival.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Tisagenlecleucel was associated with durable remission and long-term persistence for younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to the results of a multicenter, multicontinent, phase 2 trial published in the New England Journal of Medicine.

Shannon L. Maude, MD, PhD, of the Children’s Hospital of Philadelphia and her coauthors reported that the anti-CD19 chimeric antigen receptor (CAR) therapy was highly toxic, but the effects were usually mitigated. Additionally, the investigators showed feasibility of a global supply chain for distribution of the therapy.

The investigators evaluated data from 75 patients with at least 5% lymphoblasts in their bone marrow at the time of screening. Patients were aged 3 years or older at the time of screening but were no older than 21 years of age at the time of diagnosis.

For 50 patients evaluated at the interim analysis, the primary endpoint of overall remission at 3 months was met, and the overall remission rate was 82% (P less than .001).

An updated analysis showed that 81% of 75 patients who had at least 3 months of follow-up experienced overall remission (95% confidence interval, 71-89). A total of 45 of those patients experienced complete remission, and 16 had complete remission with incomplete hematologic recovery.

Event-free survival was experienced by 73% of patients at 6 months and 50% of patients at 12 months. Overall survival was 90% at 6 months and 76% at 12 months, the investigators reported.

Before tisagenlecleucel infusion, 96% of patients received lymphodepleting chemotherapy. The administration of chemotherapy was not done at the discretion of the investigator if a patient had leukopenia.

The median duration of remission was not reached, and the persistence of tisagenlecleucel in the blood was observed for as long as 20 months.

“The remissions were durable, with a 6-month relapse-free survival rate of 80%,” the investigators wrote. “The durability of the clinical response was associated with persistence of tisagenlecleucel in peripheral blood and with persistent B-cell aplasia.”

The phase 1 study of tisagenlecleucel infusion therapy for younger patients with B-cell ALL showed the toxic nature of the therapy, so investigators were not surprised by the safety data they found. Nearly three-quarters of patients who were evaluated in the study experienced a grade 3 or 4 tisagenlecleucel-related adverse event. Cytokine release syndrome occurred in 77% of patients.

Previously reported data regarding anti-CD19 CAR T-cell therapy for ALL came from single-center studies where manufacturing occurred on site, but the current study employed a global, multicenter supply chain, according to the investigators.

“The toxicity and efficacy of tisagenlecleucel [in this study] were consistent with those in the single-center study, and the feasibility of a global supply chain was demonstrated,” they wrote. “Because this study used cryopreserved leukapheresis product, it did not require fresh product and an open manufacture slot for enrollment.”

This research was sponsored and designed by Novartis Pharmaceuticals. Dr. Maude reported having received personal fees from Novartis as well as grant funding from St. Baldrick’s Foundation.
 

[email protected]

SOURCE: Maude SL, et al. N Engl J Med. 2018;378:439-48.

Tisagenlecleucel was associated with durable remission and long-term persistence for younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to the results of a multicenter, multicontinent, phase 2 trial published in the New England Journal of Medicine.

Shannon L. Maude, MD, PhD, of the Children’s Hospital of Philadelphia and her coauthors reported that the anti-CD19 chimeric antigen receptor (CAR) therapy was highly toxic, but the effects were usually mitigated. Additionally, the investigators showed feasibility of a global supply chain for distribution of the therapy.

The investigators evaluated data from 75 patients with at least 5% lymphoblasts in their bone marrow at the time of screening. Patients were aged 3 years or older at the time of screening but were no older than 21 years of age at the time of diagnosis.

For 50 patients evaluated at the interim analysis, the primary endpoint of overall remission at 3 months was met, and the overall remission rate was 82% (P less than .001).

An updated analysis showed that 81% of 75 patients who had at least 3 months of follow-up experienced overall remission (95% confidence interval, 71-89). A total of 45 of those patients experienced complete remission, and 16 had complete remission with incomplete hematologic recovery.

Event-free survival was experienced by 73% of patients at 6 months and 50% of patients at 12 months. Overall survival was 90% at 6 months and 76% at 12 months, the investigators reported.

Before tisagenlecleucel infusion, 96% of patients received lymphodepleting chemotherapy. The administration of chemotherapy was not done at the discretion of the investigator if a patient had leukopenia.

The median duration of remission was not reached, and the persistence of tisagenlecleucel in the blood was observed for as long as 20 months.

“The remissions were durable, with a 6-month relapse-free survival rate of 80%,” the investigators wrote. “The durability of the clinical response was associated with persistence of tisagenlecleucel in peripheral blood and with persistent B-cell aplasia.”

The phase 1 study of tisagenlecleucel infusion therapy for younger patients with B-cell ALL showed the toxic nature of the therapy, so investigators were not surprised by the safety data they found. Nearly three-quarters of patients who were evaluated in the study experienced a grade 3 or 4 tisagenlecleucel-related adverse event. Cytokine release syndrome occurred in 77% of patients.

Previously reported data regarding anti-CD19 CAR T-cell therapy for ALL came from single-center studies where manufacturing occurred on site, but the current study employed a global, multicenter supply chain, according to the investigators.

“The toxicity and efficacy of tisagenlecleucel [in this study] were consistent with those in the single-center study, and the feasibility of a global supply chain was demonstrated,” they wrote. “Because this study used cryopreserved leukapheresis product, it did not require fresh product and an open manufacture slot for enrollment.”

This research was sponsored and designed by Novartis Pharmaceuticals. Dr. Maude reported having received personal fees from Novartis as well as grant funding from St. Baldrick’s Foundation.
 

[email protected]

SOURCE: Maude SL, et al. N Engl J Med. 2018;378:439-48.

Tisagenlecleucel was associated with durable remission and long-term persistence for younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to the results of a multicenter, multicontinent, phase 2 trial published in the New England Journal of Medicine.

Shannon L. Maude, MD, PhD, of the Children’s Hospital of Philadelphia and her coauthors reported that the anti-CD19 chimeric antigen receptor (CAR) therapy was highly toxic, but the effects were usually mitigated. Additionally, the investigators showed feasibility of a global supply chain for distribution of the therapy.

The investigators evaluated data from 75 patients with at least 5% lymphoblasts in their bone marrow at the time of screening. Patients were aged 3 years or older at the time of screening but were no older than 21 years of age at the time of diagnosis.

For 50 patients evaluated at the interim analysis, the primary endpoint of overall remission at 3 months was met, and the overall remission rate was 82% (P less than .001).

An updated analysis showed that 81% of 75 patients who had at least 3 months of follow-up experienced overall remission (95% confidence interval, 71-89). A total of 45 of those patients experienced complete remission, and 16 had complete remission with incomplete hematologic recovery.

Event-free survival was experienced by 73% of patients at 6 months and 50% of patients at 12 months. Overall survival was 90% at 6 months and 76% at 12 months, the investigators reported.

Before tisagenlecleucel infusion, 96% of patients received lymphodepleting chemotherapy. The administration of chemotherapy was not done at the discretion of the investigator if a patient had leukopenia.

The median duration of remission was not reached, and the persistence of tisagenlecleucel in the blood was observed for as long as 20 months.

“The remissions were durable, with a 6-month relapse-free survival rate of 80%,” the investigators wrote. “The durability of the clinical response was associated with persistence of tisagenlecleucel in peripheral blood and with persistent B-cell aplasia.”

The phase 1 study of tisagenlecleucel infusion therapy for younger patients with B-cell ALL showed the toxic nature of the therapy, so investigators were not surprised by the safety data they found. Nearly three-quarters of patients who were evaluated in the study experienced a grade 3 or 4 tisagenlecleucel-related adverse event. Cytokine release syndrome occurred in 77% of patients.

Previously reported data regarding anti-CD19 CAR T-cell therapy for ALL came from single-center studies where manufacturing occurred on site, but the current study employed a global, multicenter supply chain, according to the investigators.

“The toxicity and efficacy of tisagenlecleucel [in this study] were consistent with those in the single-center study, and the feasibility of a global supply chain was demonstrated,” they wrote. “Because this study used cryopreserved leukapheresis product, it did not require fresh product and an open manufacture slot for enrollment.”

This research was sponsored and designed by Novartis Pharmaceuticals. Dr. Maude reported having received personal fees from Novartis as well as grant funding from St. Baldrick’s Foundation.
 

[email protected]

SOURCE: Maude SL, et al. N Engl J Med. 2018;378:439-48.

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.