Leukemia, Myelodysplasia, Transplantation

Photo by William Weinert

Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).

The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.

The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.

The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.

The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).

The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.

The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).

Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.

The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.

Photo by William Weinert

Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).

The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.

The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.

The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.

The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).

The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.

The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).

Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.

The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.

Photo by William Weinert

Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).

The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.

The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.

The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.

The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).

The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.

The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).

Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.

The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Photo by Bill Branson

Two companies have announced the US launch of a generic busulfan product, Myleran Injection.

Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.

The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.

Photo by Bill Branson

Two companies have announced the US launch of a generic busulfan product, Myleran Injection.

Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.

The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.

Photo by Bill Branson

Two companies have announced the US launch of a generic busulfan product, Myleran Injection.

Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.

The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.

“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.

Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.

For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).

The authors caution, however, that the recommendation applies to adults only.

Other updated recommendations include:

• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.

• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.

“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.

They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.

To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.

The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.

The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
 

A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.

“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.

Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.

For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).

The authors caution, however, that the recommendation applies to adults only.

Other updated recommendations include:

• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.

• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.

“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.

They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.

To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.

The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.

The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
 

A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.

“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.

Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.

For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).

The authors caution, however, that the recommendation applies to adults only.

Other updated recommendations include:

• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.

• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.

“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.

They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.

To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.

The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.

The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
 

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.