Hematologic Malignancies

Purpose: Multiple myeloma and solid tumor metastases can cause bone disease leading to skeletal-related events (SREs) such as bone pain, fractures, and spinal cord compression. Intravenous bisphosphonate therapy—which is indicated in such cases—can lead to osteonecrosis of the jaw and hypocalcemia further putting patients at risk for SREs. These risks can be avoided by dental evaluation before bisphosphonate therapy and calcium and vitamin D supplementation throughout treatment. Our study of veterans treated with bisphosphonates for bone metastases or multiple myeloma aimed to (1) assess screening dental evaluation prior to treatment; and (2) measure effectiveness of calcium and vitamin D supplementation.

Methods: We performed a retrospective chart review at the James J. Peters VAMC of 117 veterans with multiple myeloma or bone metastases who received intravenous bisphosphonate therapy between January 2008 and November 2013. Those receiving bisphosphonates for other morbidities such as osteoporosis or hypercalcemia were excluded. Those getting dental clearance before intravenous bisphosphonate therapy and supplementation of vitamin D and calcium were assessed. Charts were further reviewed to gather outcomes data on incidence of osteonecrosis of the jaw and SREs such as bone pain, pathologic and traumatic fractures, orthopedic surgery, spine or nerve root compression. These data were analyzed using descriptive statistics to calculate frequencies, mean/median, and proportions. Odds ratios were calculated to assess differences in SRE outcomes for those who received supplementation as compared to those who did not get supplementation with calcium and vitamin D.

Results: Of the 117 patients included in the study, 97% were males aged from 58 to 92 years. Of these, 55 (47%) had prostate cancer, 21 (17%) had multiple myeloma, and 16 (14%) had lung cancer. All patients receiving bisphosphonates for bone metastases had undergone a dental evaluation prior to starting therapy; none were reported to have osteonecrosis of the jaw. However, only 78% had vitamin D levels checked before therapy; 69% of these were vitamin D deficient and received vitamin D supplementation. Overall, rates of calcium and vitamin D supplementation were very low (34% and 41%, respectively). Fifty-four percent of the patients reported an SRE; 49% with bone pain, 13% with pathological fractures, 7% with traumatic fractures, and 8% with nerve root compression. Vitamin D supplementation significantly reduced the odds of an SRE for our patients (OR 0.37, 95% CI = 0.19- 0.74, P < .05).

Conclusions: Onset of SREs can be reduced or delayed with bisphosphonates; however, patients need prior screening for osteonecrosis of the jaw and optimized calcium and vitamin D levels. Our study showed that although screening for osteonecrosis of the jaw was at optimum levels, supplementation with calcium and vitamin D was lacking in patients on bisphosphonates. In our study, vitamin D supplementation reduced the risk of an SRE by 63%. Hence, adequate prevention with vitamin D supplementation can improve bone health among veterans with multiple myeloma or bone metastases. Data-based policies and practices need to be incorporated to provide care to ensure adequate bone health.

Purpose: Multiple myeloma and solid tumor metastases can cause bone disease leading to skeletal-related events (SREs) such as bone pain, fractures, and spinal cord compression. Intravenous bisphosphonate therapy—which is indicated in such cases—can lead to osteonecrosis of the jaw and hypocalcemia further putting patients at risk for SREs. These risks can be avoided by dental evaluation before bisphosphonate therapy and calcium and vitamin D supplementation throughout treatment. Our study of veterans treated with bisphosphonates for bone metastases or multiple myeloma aimed to (1) assess screening dental evaluation prior to treatment; and (2) measure effectiveness of calcium and vitamin D supplementation.

Methods: We performed a retrospective chart review at the James J. Peters VAMC of 117 veterans with multiple myeloma or bone metastases who received intravenous bisphosphonate therapy between January 2008 and November 2013. Those receiving bisphosphonates for other morbidities such as osteoporosis or hypercalcemia were excluded. Those getting dental clearance before intravenous bisphosphonate therapy and supplementation of vitamin D and calcium were assessed. Charts were further reviewed to gather outcomes data on incidence of osteonecrosis of the jaw and SREs such as bone pain, pathologic and traumatic fractures, orthopedic surgery, spine or nerve root compression. These data were analyzed using descriptive statistics to calculate frequencies, mean/median, and proportions. Odds ratios were calculated to assess differences in SRE outcomes for those who received supplementation as compared to those who did not get supplementation with calcium and vitamin D.

Results: Of the 117 patients included in the study, 97% were males aged from 58 to 92 years. Of these, 55 (47%) had prostate cancer, 21 (17%) had multiple myeloma, and 16 (14%) had lung cancer. All patients receiving bisphosphonates for bone metastases had undergone a dental evaluation prior to starting therapy; none were reported to have osteonecrosis of the jaw. However, only 78% had vitamin D levels checked before therapy; 69% of these were vitamin D deficient and received vitamin D supplementation. Overall, rates of calcium and vitamin D supplementation were very low (34% and 41%, respectively). Fifty-four percent of the patients reported an SRE; 49% with bone pain, 13% with pathological fractures, 7% with traumatic fractures, and 8% with nerve root compression. Vitamin D supplementation significantly reduced the odds of an SRE for our patients (OR 0.37, 95% CI = 0.19- 0.74, P < .05).

Conclusions: Onset of SREs can be reduced or delayed with bisphosphonates; however, patients need prior screening for osteonecrosis of the jaw and optimized calcium and vitamin D levels. Our study showed that although screening for osteonecrosis of the jaw was at optimum levels, supplementation with calcium and vitamin D was lacking in patients on bisphosphonates. In our study, vitamin D supplementation reduced the risk of an SRE by 63%. Hence, adequate prevention with vitamin D supplementation can improve bone health among veterans with multiple myeloma or bone metastases. Data-based policies and practices need to be incorporated to provide care to ensure adequate bone health.

Purpose: Multiple myeloma and solid tumor metastases can cause bone disease leading to skeletal-related events (SREs) such as bone pain, fractures, and spinal cord compression. Intravenous bisphosphonate therapy—which is indicated in such cases—can lead to osteonecrosis of the jaw and hypocalcemia further putting patients at risk for SREs. These risks can be avoided by dental evaluation before bisphosphonate therapy and calcium and vitamin D supplementation throughout treatment. Our study of veterans treated with bisphosphonates for bone metastases or multiple myeloma aimed to (1) assess screening dental evaluation prior to treatment; and (2) measure effectiveness of calcium and vitamin D supplementation.

Methods: We performed a retrospective chart review at the James J. Peters VAMC of 117 veterans with multiple myeloma or bone metastases who received intravenous bisphosphonate therapy between January 2008 and November 2013. Those receiving bisphosphonates for other morbidities such as osteoporosis or hypercalcemia were excluded. Those getting dental clearance before intravenous bisphosphonate therapy and supplementation of vitamin D and calcium were assessed. Charts were further reviewed to gather outcomes data on incidence of osteonecrosis of the jaw and SREs such as bone pain, pathologic and traumatic fractures, orthopedic surgery, spine or nerve root compression. These data were analyzed using descriptive statistics to calculate frequencies, mean/median, and proportions. Odds ratios were calculated to assess differences in SRE outcomes for those who received supplementation as compared to those who did not get supplementation with calcium and vitamin D.

Results: Of the 117 patients included in the study, 97% were males aged from 58 to 92 years. Of these, 55 (47%) had prostate cancer, 21 (17%) had multiple myeloma, and 16 (14%) had lung cancer. All patients receiving bisphosphonates for bone metastases had undergone a dental evaluation prior to starting therapy; none were reported to have osteonecrosis of the jaw. However, only 78% had vitamin D levels checked before therapy; 69% of these were vitamin D deficient and received vitamin D supplementation. Overall, rates of calcium and vitamin D supplementation were very low (34% and 41%, respectively). Fifty-four percent of the patients reported an SRE; 49% with bone pain, 13% with pathological fractures, 7% with traumatic fractures, and 8% with nerve root compression. Vitamin D supplementation significantly reduced the odds of an SRE for our patients (OR 0.37, 95% CI = 0.19- 0.74, P < .05).

Conclusions: Onset of SREs can be reduced or delayed with bisphosphonates; however, patients need prior screening for osteonecrosis of the jaw and optimized calcium and vitamin D levels. Our study showed that although screening for osteonecrosis of the jaw was at optimum levels, supplementation with calcium and vitamin D was lacking in patients on bisphosphonates. In our study, vitamin D supplementation reduced the risk of an SRE by 63%. Hence, adequate prevention with vitamin D supplementation can improve bone health among veterans with multiple myeloma or bone metastases. Data-based policies and practices need to be incorporated to provide care to ensure adequate bone health.

Purpose: Familial clusters of either myelodysplasia (MDS) or myelofibrosis (MF) are well documented although uncommon. The inheritance of a somatic driver mutation presumably accounts for these kindreds, and DNA sequencing has revealed multiple candidate mutations (JAK2, ASXL1, TET2, EZH2, SRSF2) that are shared across the spectrum of these disorders. Given this overlap of nonrandom mutations in MDS and MF, it is surprising that clusters of both MDS and MF within the same family seem to be very rare. Recently, however, we observed a woman with MDS who reported a deceased sibling with MDS and a deceased paternal uncle with MF.

Methods: A careful family history and a review of the medical records, archived pathology, and clinical course were performed and compared with that of the index case.

Results: The index case is a woman aged 49 years presenting with severe anemia in July 2013. A bone marrow (BM) biopsy was mildly hypocellular with reduced erythroid maturation, dyspoietic hypolobated megakaryocytes and no increase in blasts. Cytogenetics revealed an isolated del(5)(q13q31) (in 20/20 cells) with del(7q) in 3/20 cells. Lenalidomide therapy resulted in initial transfusion independence. The deceased brother presented April 1994 with weakness at age 39. A CBC showed pancytopenia with a few blasts and nucleated rbc. A BM biopsy revealed predominantly extreme erythroid megaloblastosis with marked nuclear atypia, hypolobated megakaryocytes without fibrosis, mildly dyspoietic myeloid maturation, and 5% nonerythroid CD34+ blasts. Complex cytogenetic changes included monosomy 7 and der(5), likely a functional 5q deletion or duplication. Despite transfusion support, the patient died of infection and CNS hemorrhage after several months. The paternal uncle presented in June 1996 at age 60 with anemia. The CBC showed leukoerythro-blastosis with prominent dacrocytes, mild thrombo-cytopenia but no dyspoiesis. A BM biopsy revealed marked fibrosis, prominent osteosclerosis, and large hyperlobated hyperchromatic megakaryo-cytes. Overall the history, blood, and biopsy findings were consistent with primary MF but not MDS with fibrosis. Death occurred after 3 years of transfusion support.

Conclusions: Despite the extreme rarity of reported MDS and MF cases within a single family, the kindred reported here suggests the existence of an inherited gene defect that increases the risk of developing either MDS or MF. Presumably, the onset of clinically evident disease and its eventual phenotype is determined by the accumulation of additional different secondary genetic changes. The lack of disease in 6 other siblings and the deceased father aged 75 years, however, argues that any hypothetical driver mutation has incomplete penetrance, ie, a reduced likelihood of either disorder developing within a lifetime. Moreover, since this report cannot rule out either chance alone or a common environmental etiology despite substantial age and household differences, DNA sequencing studies will be necessary to identify a putative inherited gene mutation driving the development of both MDS or MF in this unusual kindred.

Purpose: Familial clusters of either myelodysplasia (MDS) or myelofibrosis (MF) are well documented although uncommon. The inheritance of a somatic driver mutation presumably accounts for these kindreds, and DNA sequencing has revealed multiple candidate mutations (JAK2, ASXL1, TET2, EZH2, SRSF2) that are shared across the spectrum of these disorders. Given this overlap of nonrandom mutations in MDS and MF, it is surprising that clusters of both MDS and MF within the same family seem to be very rare. Recently, however, we observed a woman with MDS who reported a deceased sibling with MDS and a deceased paternal uncle with MF.

Methods: A careful family history and a review of the medical records, archived pathology, and clinical course were performed and compared with that of the index case.

Results: The index case is a woman aged 49 years presenting with severe anemia in July 2013. A bone marrow (BM) biopsy was mildly hypocellular with reduced erythroid maturation, dyspoietic hypolobated megakaryocytes and no increase in blasts. Cytogenetics revealed an isolated del(5)(q13q31) (in 20/20 cells) with del(7q) in 3/20 cells. Lenalidomide therapy resulted in initial transfusion independence. The deceased brother presented April 1994 with weakness at age 39. A CBC showed pancytopenia with a few blasts and nucleated rbc. A BM biopsy revealed predominantly extreme erythroid megaloblastosis with marked nuclear atypia, hypolobated megakaryocytes without fibrosis, mildly dyspoietic myeloid maturation, and 5% nonerythroid CD34+ blasts. Complex cytogenetic changes included monosomy 7 and der(5), likely a functional 5q deletion or duplication. Despite transfusion support, the patient died of infection and CNS hemorrhage after several months. The paternal uncle presented in June 1996 at age 60 with anemia. The CBC showed leukoerythro-blastosis with prominent dacrocytes, mild thrombo-cytopenia but no dyspoiesis. A BM biopsy revealed marked fibrosis, prominent osteosclerosis, and large hyperlobated hyperchromatic megakaryo-cytes. Overall the history, blood, and biopsy findings were consistent with primary MF but not MDS with fibrosis. Death occurred after 3 years of transfusion support.

Conclusions: Despite the extreme rarity of reported MDS and MF cases within a single family, the kindred reported here suggests the existence of an inherited gene defect that increases the risk of developing either MDS or MF. Presumably, the onset of clinically evident disease and its eventual phenotype is determined by the accumulation of additional different secondary genetic changes. The lack of disease in 6 other siblings and the deceased father aged 75 years, however, argues that any hypothetical driver mutation has incomplete penetrance, ie, a reduced likelihood of either disorder developing within a lifetime. Moreover, since this report cannot rule out either chance alone or a common environmental etiology despite substantial age and household differences, DNA sequencing studies will be necessary to identify a putative inherited gene mutation driving the development of both MDS or MF in this unusual kindred.

Purpose: Familial clusters of either myelodysplasia (MDS) or myelofibrosis (MF) are well documented although uncommon. The inheritance of a somatic driver mutation presumably accounts for these kindreds, and DNA sequencing has revealed multiple candidate mutations (JAK2, ASXL1, TET2, EZH2, SRSF2) that are shared across the spectrum of these disorders. Given this overlap of nonrandom mutations in MDS and MF, it is surprising that clusters of both MDS and MF within the same family seem to be very rare. Recently, however, we observed a woman with MDS who reported a deceased sibling with MDS and a deceased paternal uncle with MF.

Methods: A careful family history and a review of the medical records, archived pathology, and clinical course were performed and compared with that of the index case.

Results: The index case is a woman aged 49 years presenting with severe anemia in July 2013. A bone marrow (BM) biopsy was mildly hypocellular with reduced erythroid maturation, dyspoietic hypolobated megakaryocytes and no increase in blasts. Cytogenetics revealed an isolated del(5)(q13q31) (in 20/20 cells) with del(7q) in 3/20 cells. Lenalidomide therapy resulted in initial transfusion independence. The deceased brother presented April 1994 with weakness at age 39. A CBC showed pancytopenia with a few blasts and nucleated rbc. A BM biopsy revealed predominantly extreme erythroid megaloblastosis with marked nuclear atypia, hypolobated megakaryocytes without fibrosis, mildly dyspoietic myeloid maturation, and 5% nonerythroid CD34+ blasts. Complex cytogenetic changes included monosomy 7 and der(5), likely a functional 5q deletion or duplication. Despite transfusion support, the patient died of infection and CNS hemorrhage after several months. The paternal uncle presented in June 1996 at age 60 with anemia. The CBC showed leukoerythro-blastosis with prominent dacrocytes, mild thrombo-cytopenia but no dyspoiesis. A BM biopsy revealed marked fibrosis, prominent osteosclerosis, and large hyperlobated hyperchromatic megakaryo-cytes. Overall the history, blood, and biopsy findings were consistent with primary MF but not MDS with fibrosis. Death occurred after 3 years of transfusion support.

Conclusions: Despite the extreme rarity of reported MDS and MF cases within a single family, the kindred reported here suggests the existence of an inherited gene defect that increases the risk of developing either MDS or MF. Presumably, the onset of clinically evident disease and its eventual phenotype is determined by the accumulation of additional different secondary genetic changes. The lack of disease in 6 other siblings and the deceased father aged 75 years, however, argues that any hypothetical driver mutation has incomplete penetrance, ie, a reduced likelihood of either disorder developing within a lifetime. Moreover, since this report cannot rule out either chance alone or a common environmental etiology despite substantial age and household differences, DNA sequencing studies will be necessary to identify a putative inherited gene mutation driving the development of both MDS or MF in this unusual kindred.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy in the U.S. with 15,000 new patients diagnosed each year.¹ This leukemia is frequently diagnosed in veterans since it is more commonly seen in an elderly male population. The disease is characterized by a slow accumulation of mature B cells that are functionally incompetent and resist apoptosis. CLL has an indolent clinical course, but about 60% to 70% of patients require treatment. The disease also runs a variable course, and a number of genetic abnormalities and prognostic markers have been defined to subclassify CLL patients and prognosticate.^2-4 This article reviews important CLL signaling pathways and novel therapeutic agents in this leukemia.

Signaling Pathways

B-Cell Receptor Signaling

The B-cell receptor (BCR) signaling is the major signaling pathway in CLL, because it defines clinical, biologic, and prognostic characteristics of the disease.⁵ The BCR is composed of a surface transmembrane immunoglobulin that binds the antigen with CD79 alpha and beta chains. The activation of BCR results in the formation of a signaling complex or signalosome, which includes Lyn, Syk, BTK, and ZAP-70, among other components that assemble with other adaptor proteins (Figure). This assembly of proteins occurs on the cytoplasmic tails of immunoglobulin chains on regions called immunoreceptor tyrosine-based motifs (ITAMs).

With the assembly of this signaling complex, BCR stimulates a number of downstream pathways,  such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), protein kinase C, nuclear factor-κB (NFκB), and extracellular signal-regulated kinases (ERKs) (Figure). Activation of these pathways results in cell proliferation, resistance to apoptosis, increased cell motility and migration. Recent studies have identified additional novel components of this signaling complex, including a guanine nucleotide exchange factor (GEF) RASGRF1. This GEF is activated by BCR signaling and, in turn, stimulates the ERK pathway by increasing the production of active GTP-bound Ras.⁶

The ability of BCR to activate a number of downstream signaling pathways makes it a highly relevant and investigated pathway in this leukemia. Inhibitors have been developed and/or identified against a number of signalosome components to block the BCR signaling.⁷ Syk and Lyn are Src kinases, and their phosphorylation is one of the initial events of BCR signaling. Syk is overexpressed in CLL specimens, and Syk inhibitors (R406 and P505-15, also known as PRT062607) have shown activity in CLL.^8,9 Dasatinib is a Src inhibitor that also shows activity in CLL specimens and is being studied in combination with chemotherapy drugs in refractory CLL patients.¹⁰

BTK, a component of the BCR signalosome, is required for BCR function, and loss of its function is seen in X-linked agammaglobulinemia. PCI-32765 (ibrutinib) is an oral BTK inhibitor that irreversibly inactivates this kinase and has been approved for clinical use in CLL patients.^11,12 Another signaling pathway activated by BCR is the PI3K, and a promising inhibitor (CAL-101) blocks its activity in CLL specimens.¹³ Investigative work has identified that the delta isoform of PI3K p110 is highly expressed in B cells and lymphocytes.¹⁴ This is a catalytic subunit of a class I PI3K with a role in BCR signaling. A selective inhibitor GS-1101 (CAL-101) is able to block PI3K signaling in CLL specimens and inhibits Akt phosphorylation and other downstream effectors along with induction of apoptosis.¹⁵ The clinical data with BTK and PI3K inhibitors will be discussed later in this review.

CLL and the Microenvironment

Interactions between CLL cells and the microenvironment allow CLL cells to thrive in certain niche environments.^16,17 Interaction mainly occurs via bone marrow stromal cells and nurselike cells (NLCs), which evolve from monocytes (Figure). These interactions can be divided into 2 groups. First, CLL cell growth is supported by a number of chemokine receptor-ligand interactions. CXCR4 is the receptor for CXCL12 (SDF-1) that stimulates chemotaxis and tissue homing. Another chemokine is CXCL13, which acts via its receptor CXCR5 and is involved in chemotaxis and activation of other kinases. Second, NLCs also support CLL cells by expressing TNF family members BAFF and APRIL, which interact with their receptors and activate the NFκB pathway.

Leukemic cells also express VLA-4 integrins, which further their support adhesion to the stromal cells and predict for an aggressive phenotype. Specific inhibitors that block the stimulation by chemokines and cytokines are not yet available; however, one can envision that this class of inhibitors will decrease the chemoresistance of leukemic cells and will be used in conjunction with other chemotherapy agents. Interestingly, inhibitors that block BCR-mediated signaling (BTK and PI3K inhibitors) also inhibit signaling via the microenvironment and chemokines.

Wnt-β-catenin Pathway

Wnt signaling affects developmental pathways, and its aberrant activation has major oncogenic effects as well. This pathway is activated in CLL as these leukemic cells express high levels of Wnt and frizzled along with epigenetic downregulation of Wnt pathway antagonist genes, including secreted frizzled-related protein (SFRP) family members and WIF1 (Figure).^18-20 The binding of Wnts to their cognate receptors results in inhibition of GSK3β phosphorylation and stabilization of β-catenin, which then translocates to the nucleus and interacts with lymphoid-enhancing (LEF) and T-cell transcription factors to activate transcription of Wnt-target genes. Lack of E-cadherin expression in CLL cells also results in an increase in translocation of β-catenin and upregulation of the Wnt pathway.²⁰

Wnt-target genes include Myc, LEF, cyclinD1, COX-2, and MMP. Gene expression profiling from our laboratory and other groups have identified the overexpression of these wnt-target genes and support this pathway activation in CLL cells.²⁰ This is a promising signalling pathway and an active area of research for developing inhibitors that will have a growth inhibitory effect on CLL leukemic cells. GSK3b inhibitors and other drugs that re-express epigenetically silenced Wnt antagonist genes have been shown to inhibit this pathway activity in CLL cells in vitro.

Notch Pathway Activation

High-throughput exome sequencing has identified recurring mutations in a number of genes, including NOTCH1.²¹ Analysis of additional CLL patients confirmed activating NOTCH1 mutations in 10% to 15% of CLL patients and were also associated with poor outcome.²² This pathway is activated by ligands such as Jagged and Delta-like, which interact with the Notch receptor, which is then cleaved by γ-secretases. The cleaved intracellular domain of the NOTCH1 receptor in combination with other factors activates transcription of target genes, including Myc and HES1 (Figure). Besides the mutations that generate a truncated protein or may stabilize the pathway, the Notch pathway is also constitutively active in CLL specimens.²³ Notch stimulation increases activity of prosurvival pathways and genes such as NFκB that resist apoptotic signals. The pathway can be inhibited by γ-secretase inhibitors (GSIs), which reduce the levels of cleaved NOTCH1 protein and downregulated Notch target genes. This pathway is also able to modulate the microenvironment stimuli as the GSIs inhibit responses to chemokines such as CXCL12 and inhibit migration and invasion.²⁴

Newer Theraputic Agents

Work on signaling mechanisms paid dividends in CLL with the recent development of 2 inhibitors. Ibrutinib (BTK inhibitor) and idelalisib (PI3K inhibitor) are being studied in clinical trials, and both drugs block the BCR and microenvironment signaling pathways, thereby inhibiting the growth of CLL cells.

BTK Inhibitor: Ibrutinib

The activity of BTK is critical for a number of CLL signaling pathways, and it is a component of the initial signaling complex or signalosome that is formed with BCR signaling. Studies have shown that inhibiting this kinase blocks a number of pathways, including ERK, NFκB, and others. The drug ibrutinib blocks this kinase by forming a covalent bond and inhibiting its enzyme activity. This orally bioavailable drug showed activity in phase 1 trials in different B-cell malignancies.²⁵ In a phase 2 study, high-risk CLL patients were given 2 different doses of this inhibitor, and the overall response rate was 71% with an overall survival at 26 months of 83%.¹¹ Responses were seen in all patients irrespective of clinical and genetic risk factors. Based on these findings, the drug was approved for clinical use in patients with relapsed or refractory disease. Recently, there are data on the use of this drug as frontline therapy in elderly patients, and the drug was well tolerated.²⁶ There are additional ongoing trials to compare this drug with other agents, including chlorambucil (in chemotherapy-naïve patients) and ofatumumab (in relapsed or refractory patients).

PI3 Kinase p110 Delta Inhibitor: Idelalisib

The crucial finding for the development of this inhibitor was the over-expression of the delta isoform of PI3K p110 in B-cell malignancies.¹⁴ The drug CAL-101 selectively inhibits this constitutively active isoform and induces apoptosis in a number of B-cell malignancies.^15,27 In the phase 1 trial, this inhibitor was evaluated in relapsed/refractory patients at multiple dose levels.²⁸ There was inhibition of PI3K signaling with an overall response rate of 72%, and a partial response rate of 39% was observed in CLL patients. This was followed by a randomized, placebo-controlled phase 3 study in which patients with myelosuppression, decreased renal function, or other illnesses were treated with either rituximab alone or with rituximab and idelalisib.²⁹

At the time of reporting, the median progression-free survival (PFS) was 5.5 months in the placebo arm and was not reached in the idelalisib arm. Overall response rates were higher in the idelalisib group (81% vs 13%) with similar toxicity profiles in the 2 groups. This drug is now being extensively studied in combination with bendamustine and other anti-CD20 antibodies in clinical trials.

A unique toxicity observed with both these inhibitors is the initial lymphocytosis. In the case of ibrutinib, this was seen in a majority of patients (77%) and at the same time there was a response in the nodal disease, implying a redistribution of leukemic cells from the tissues to the peripheral blood.³⁰

A potential explanation is that these drugs inhibit signaling via chemokines and other components of the microenvironment and by inhibiting the homing signals, allows leukemic cells to move out of their niche areas. This was analyzed in a recent study that compared clinical and biochemical parameters of patients who had a complete or partial response with ibrutinib compared with a “partial response except for lymphocytosis.”³⁰ Patients with “partial response except for lymphocytosis” were found to have favorable prognostic factors, and the persisting leukemic cells were not clonally different from the original cells. The progression free survival of patients with “partial response except for lymphocytosis” was also similar to the subgroup with no prolonged lymphocytosis.

Discussion

Several therapeutic agents with novel mechanisms of action are effective in killing the CLL leukemic cells, and a number of targeted agents are currently in the pipeline. The next challenge for treating CLL will be the proper integration of these novel targeted agents with the traditional chemotherapy and chemoimmunotherapy approaches. Let us consider CLL patients in different clinical settings. First, a patient aged 60 years who is otherwise healthy will be treated with possibly all the available chemotherapy and chemoimmunotherapy options, as well as the newer targeted agents. In this clinical setting sequencing of therapy is not a major concern. On the other hand, a patient aged 70 years who is already refractory to multiple lines of therapy is a good candidate for these newer drugs.

The more controversial use of these targeted agents will be in an older patient with some comorbidities and newly diagnosed CLL. In this clinical setting, should one go with traditional chemotherapy/chemoimmunotherapy approaches or consider newer targeted agents? These issues are now being addressed in clinical trials, and with acceptable toxicity profiles these newer drugs will move to the frontline setting.  

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations­–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy in the U.S. with 15,000 new patients diagnosed each year.¹ This leukemia is frequently diagnosed in veterans since it is more commonly seen in an elderly male population. The disease is characterized by a slow accumulation of mature B cells that are functionally incompetent and resist apoptosis. CLL has an indolent clinical course, but about 60% to 70% of patients require treatment. The disease also runs a variable course, and a number of genetic abnormalities and prognostic markers have been defined to subclassify CLL patients and prognosticate.^2-4 This article reviews important CLL signaling pathways and novel therapeutic agents in this leukemia.

Signaling Pathways

B-Cell Receptor Signaling

The B-cell receptor (BCR) signaling is the major signaling pathway in CLL, because it defines clinical, biologic, and prognostic characteristics of the disease.⁵ The BCR is composed of a surface transmembrane immunoglobulin that binds the antigen with CD79 alpha and beta chains. The activation of BCR results in the formation of a signaling complex or signalosome, which includes Lyn, Syk, BTK, and ZAP-70, among other components that assemble with other adaptor proteins (Figure). This assembly of proteins occurs on the cytoplasmic tails of immunoglobulin chains on regions called immunoreceptor tyrosine-based motifs (ITAMs).

With the assembly of this signaling complex, BCR stimulates a number of downstream pathways,  such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), protein kinase C, nuclear factor-κB (NFκB), and extracellular signal-regulated kinases (ERKs) (Figure). Activation of these pathways results in cell proliferation, resistance to apoptosis, increased cell motility and migration. Recent studies have identified additional novel components of this signaling complex, including a guanine nucleotide exchange factor (GEF) RASGRF1. This GEF is activated by BCR signaling and, in turn, stimulates the ERK pathway by increasing the production of active GTP-bound Ras.⁶

The ability of BCR to activate a number of downstream signaling pathways makes it a highly relevant and investigated pathway in this leukemia. Inhibitors have been developed and/or identified against a number of signalosome components to block the BCR signaling.⁷ Syk and Lyn are Src kinases, and their phosphorylation is one of the initial events of BCR signaling. Syk is overexpressed in CLL specimens, and Syk inhibitors (R406 and P505-15, also known as PRT062607) have shown activity in CLL.^8,9 Dasatinib is a Src inhibitor that also shows activity in CLL specimens and is being studied in combination with chemotherapy drugs in refractory CLL patients.¹⁰

BTK, a component of the BCR signalosome, is required for BCR function, and loss of its function is seen in X-linked agammaglobulinemia. PCI-32765 (ibrutinib) is an oral BTK inhibitor that irreversibly inactivates this kinase and has been approved for clinical use in CLL patients.^11,12 Another signaling pathway activated by BCR is the PI3K, and a promising inhibitor (CAL-101) blocks its activity in CLL specimens.¹³ Investigative work has identified that the delta isoform of PI3K p110 is highly expressed in B cells and lymphocytes.¹⁴ This is a catalytic subunit of a class I PI3K with a role in BCR signaling. A selective inhibitor GS-1101 (CAL-101) is able to block PI3K signaling in CLL specimens and inhibits Akt phosphorylation and other downstream effectors along with induction of apoptosis.¹⁵ The clinical data with BTK and PI3K inhibitors will be discussed later in this review.

CLL and the Microenvironment

Interactions between CLL cells and the microenvironment allow CLL cells to thrive in certain niche environments.^16,17 Interaction mainly occurs via bone marrow stromal cells and nurselike cells (NLCs), which evolve from monocytes (Figure). These interactions can be divided into 2 groups. First, CLL cell growth is supported by a number of chemokine receptor-ligand interactions. CXCR4 is the receptor for CXCL12 (SDF-1) that stimulates chemotaxis and tissue homing. Another chemokine is CXCL13, which acts via its receptor CXCR5 and is involved in chemotaxis and activation of other kinases. Second, NLCs also support CLL cells by expressing TNF family members BAFF and APRIL, which interact with their receptors and activate the NFκB pathway.

Leukemic cells also express VLA-4 integrins, which further their support adhesion to the stromal cells and predict for an aggressive phenotype. Specific inhibitors that block the stimulation by chemokines and cytokines are not yet available; however, one can envision that this class of inhibitors will decrease the chemoresistance of leukemic cells and will be used in conjunction with other chemotherapy agents. Interestingly, inhibitors that block BCR-mediated signaling (BTK and PI3K inhibitors) also inhibit signaling via the microenvironment and chemokines.

Wnt-β-catenin Pathway

Wnt signaling affects developmental pathways, and its aberrant activation has major oncogenic effects as well. This pathway is activated in CLL as these leukemic cells express high levels of Wnt and frizzled along with epigenetic downregulation of Wnt pathway antagonist genes, including secreted frizzled-related protein (SFRP) family members and WIF1 (Figure).^18-20 The binding of Wnts to their cognate receptors results in inhibition of GSK3β phosphorylation and stabilization of β-catenin, which then translocates to the nucleus and interacts with lymphoid-enhancing (LEF) and T-cell transcription factors to activate transcription of Wnt-target genes. Lack of E-cadherin expression in CLL cells also results in an increase in translocation of β-catenin and upregulation of the Wnt pathway.²⁰

Wnt-target genes include Myc, LEF, cyclinD1, COX-2, and MMP. Gene expression profiling from our laboratory and other groups have identified the overexpression of these wnt-target genes and support this pathway activation in CLL cells.²⁰ This is a promising signalling pathway and an active area of research for developing inhibitors that will have a growth inhibitory effect on CLL leukemic cells. GSK3b inhibitors and other drugs that re-express epigenetically silenced Wnt antagonist genes have been shown to inhibit this pathway activity in CLL cells in vitro.

Notch Pathway Activation

High-throughput exome sequencing has identified recurring mutations in a number of genes, including NOTCH1.²¹ Analysis of additional CLL patients confirmed activating NOTCH1 mutations in 10% to 15% of CLL patients and were also associated with poor outcome.²² This pathway is activated by ligands such as Jagged and Delta-like, which interact with the Notch receptor, which is then cleaved by γ-secretases. The cleaved intracellular domain of the NOTCH1 receptor in combination with other factors activates transcription of target genes, including Myc and HES1 (Figure). Besides the mutations that generate a truncated protein or may stabilize the pathway, the Notch pathway is also constitutively active in CLL specimens.²³ Notch stimulation increases activity of prosurvival pathways and genes such as NFκB that resist apoptotic signals. The pathway can be inhibited by γ-secretase inhibitors (GSIs), which reduce the levels of cleaved NOTCH1 protein and downregulated Notch target genes. This pathway is also able to modulate the microenvironment stimuli as the GSIs inhibit responses to chemokines such as CXCL12 and inhibit migration and invasion.²⁴

Newer Theraputic Agents

Work on signaling mechanisms paid dividends in CLL with the recent development of 2 inhibitors. Ibrutinib (BTK inhibitor) and idelalisib (PI3K inhibitor) are being studied in clinical trials, and both drugs block the BCR and microenvironment signaling pathways, thereby inhibiting the growth of CLL cells.

BTK Inhibitor: Ibrutinib

The activity of BTK is critical for a number of CLL signaling pathways, and it is a component of the initial signaling complex or signalosome that is formed with BCR signaling. Studies have shown that inhibiting this kinase blocks a number of pathways, including ERK, NFκB, and others. The drug ibrutinib blocks this kinase by forming a covalent bond and inhibiting its enzyme activity. This orally bioavailable drug showed activity in phase 1 trials in different B-cell malignancies.²⁵ In a phase 2 study, high-risk CLL patients were given 2 different doses of this inhibitor, and the overall response rate was 71% with an overall survival at 26 months of 83%.¹¹ Responses were seen in all patients irrespective of clinical and genetic risk factors. Based on these findings, the drug was approved for clinical use in patients with relapsed or refractory disease. Recently, there are data on the use of this drug as frontline therapy in elderly patients, and the drug was well tolerated.²⁶ There are additional ongoing trials to compare this drug with other agents, including chlorambucil (in chemotherapy-naïve patients) and ofatumumab (in relapsed or refractory patients).

PI3 Kinase p110 Delta Inhibitor: Idelalisib

The crucial finding for the development of this inhibitor was the over-expression of the delta isoform of PI3K p110 in B-cell malignancies.¹⁴ The drug CAL-101 selectively inhibits this constitutively active isoform and induces apoptosis in a number of B-cell malignancies.^15,27 In the phase 1 trial, this inhibitor was evaluated in relapsed/refractory patients at multiple dose levels.²⁸ There was inhibition of PI3K signaling with an overall response rate of 72%, and a partial response rate of 39% was observed in CLL patients. This was followed by a randomized, placebo-controlled phase 3 study in which patients with myelosuppression, decreased renal function, or other illnesses were treated with either rituximab alone or with rituximab and idelalisib.²⁹

At the time of reporting, the median progression-free survival (PFS) was 5.5 months in the placebo arm and was not reached in the idelalisib arm. Overall response rates were higher in the idelalisib group (81% vs 13%) with similar toxicity profiles in the 2 groups. This drug is now being extensively studied in combination with bendamustine and other anti-CD20 antibodies in clinical trials.

A unique toxicity observed with both these inhibitors is the initial lymphocytosis. In the case of ibrutinib, this was seen in a majority of patients (77%) and at the same time there was a response in the nodal disease, implying a redistribution of leukemic cells from the tissues to the peripheral blood.³⁰

A potential explanation is that these drugs inhibit signaling via chemokines and other components of the microenvironment and by inhibiting the homing signals, allows leukemic cells to move out of their niche areas. This was analyzed in a recent study that compared clinical and biochemical parameters of patients who had a complete or partial response with ibrutinib compared with a “partial response except for lymphocytosis.”³⁰ Patients with “partial response except for lymphocytosis” were found to have favorable prognostic factors, and the persisting leukemic cells were not clonally different from the original cells. The progression free survival of patients with “partial response except for lymphocytosis” was also similar to the subgroup with no prolonged lymphocytosis.

Discussion

Several therapeutic agents with novel mechanisms of action are effective in killing the CLL leukemic cells, and a number of targeted agents are currently in the pipeline. The next challenge for treating CLL will be the proper integration of these novel targeted agents with the traditional chemotherapy and chemoimmunotherapy approaches. Let us consider CLL patients in different clinical settings. First, a patient aged 60 years who is otherwise healthy will be treated with possibly all the available chemotherapy and chemoimmunotherapy options, as well as the newer targeted agents. In this clinical setting sequencing of therapy is not a major concern. On the other hand, a patient aged 70 years who is already refractory to multiple lines of therapy is a good candidate for these newer drugs.

The more controversial use of these targeted agents will be in an older patient with some comorbidities and newly diagnosed CLL. In this clinical setting, should one go with traditional chemotherapy/chemoimmunotherapy approaches or consider newer targeted agents? These issues are now being addressed in clinical trials, and with acceptable toxicity profiles these newer drugs will move to the frontline setting.  

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations­–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy in the U.S. with 15,000 new patients diagnosed each year.¹ This leukemia is frequently diagnosed in veterans since it is more commonly seen in an elderly male population. The disease is characterized by a slow accumulation of mature B cells that are functionally incompetent and resist apoptosis. CLL has an indolent clinical course, but about 60% to 70% of patients require treatment. The disease also runs a variable course, and a number of genetic abnormalities and prognostic markers have been defined to subclassify CLL patients and prognosticate.^2-4 This article reviews important CLL signaling pathways and novel therapeutic agents in this leukemia.

Signaling Pathways

B-Cell Receptor Signaling

The B-cell receptor (BCR) signaling is the major signaling pathway in CLL, because it defines clinical, biologic, and prognostic characteristics of the disease.⁵ The BCR is composed of a surface transmembrane immunoglobulin that binds the antigen with CD79 alpha and beta chains. The activation of BCR results in the formation of a signaling complex or signalosome, which includes Lyn, Syk, BTK, and ZAP-70, among other components that assemble with other adaptor proteins (Figure). This assembly of proteins occurs on the cytoplasmic tails of immunoglobulin chains on regions called immunoreceptor tyrosine-based motifs (ITAMs).

With the assembly of this signaling complex, BCR stimulates a number of downstream pathways,  such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), protein kinase C, nuclear factor-κB (NFκB), and extracellular signal-regulated kinases (ERKs) (Figure). Activation of these pathways results in cell proliferation, resistance to apoptosis, increased cell motility and migration. Recent studies have identified additional novel components of this signaling complex, including a guanine nucleotide exchange factor (GEF) RASGRF1. This GEF is activated by BCR signaling and, in turn, stimulates the ERK pathway by increasing the production of active GTP-bound Ras.⁶

The ability of BCR to activate a number of downstream signaling pathways makes it a highly relevant and investigated pathway in this leukemia. Inhibitors have been developed and/or identified against a number of signalosome components to block the BCR signaling.⁷ Syk and Lyn are Src kinases, and their phosphorylation is one of the initial events of BCR signaling. Syk is overexpressed in CLL specimens, and Syk inhibitors (R406 and P505-15, also known as PRT062607) have shown activity in CLL.^8,9 Dasatinib is a Src inhibitor that also shows activity in CLL specimens and is being studied in combination with chemotherapy drugs in refractory CLL patients.¹⁰

BTK, a component of the BCR signalosome, is required for BCR function, and loss of its function is seen in X-linked agammaglobulinemia. PCI-32765 (ibrutinib) is an oral BTK inhibitor that irreversibly inactivates this kinase and has been approved for clinical use in CLL patients.^11,12 Another signaling pathway activated by BCR is the PI3K, and a promising inhibitor (CAL-101) blocks its activity in CLL specimens.¹³ Investigative work has identified that the delta isoform of PI3K p110 is highly expressed in B cells and lymphocytes.¹⁴ This is a catalytic subunit of a class I PI3K with a role in BCR signaling. A selective inhibitor GS-1101 (CAL-101) is able to block PI3K signaling in CLL specimens and inhibits Akt phosphorylation and other downstream effectors along with induction of apoptosis.¹⁵ The clinical data with BTK and PI3K inhibitors will be discussed later in this review.

CLL and the Microenvironment

Interactions between CLL cells and the microenvironment allow CLL cells to thrive in certain niche environments.^16,17 Interaction mainly occurs via bone marrow stromal cells and nurselike cells (NLCs), which evolve from monocytes (Figure). These interactions can be divided into 2 groups. First, CLL cell growth is supported by a number of chemokine receptor-ligand interactions. CXCR4 is the receptor for CXCL12 (SDF-1) that stimulates chemotaxis and tissue homing. Another chemokine is CXCL13, which acts via its receptor CXCR5 and is involved in chemotaxis and activation of other kinases. Second, NLCs also support CLL cells by expressing TNF family members BAFF and APRIL, which interact with their receptors and activate the NFκB pathway.

Leukemic cells also express VLA-4 integrins, which further their support adhesion to the stromal cells and predict for an aggressive phenotype. Specific inhibitors that block the stimulation by chemokines and cytokines are not yet available; however, one can envision that this class of inhibitors will decrease the chemoresistance of leukemic cells and will be used in conjunction with other chemotherapy agents. Interestingly, inhibitors that block BCR-mediated signaling (BTK and PI3K inhibitors) also inhibit signaling via the microenvironment and chemokines.

Wnt-β-catenin Pathway

Wnt signaling affects developmental pathways, and its aberrant activation has major oncogenic effects as well. This pathway is activated in CLL as these leukemic cells express high levels of Wnt and frizzled along with epigenetic downregulation of Wnt pathway antagonist genes, including secreted frizzled-related protein (SFRP) family members and WIF1 (Figure).^18-20 The binding of Wnts to their cognate receptors results in inhibition of GSK3β phosphorylation and stabilization of β-catenin, which then translocates to the nucleus and interacts with lymphoid-enhancing (LEF) and T-cell transcription factors to activate transcription of Wnt-target genes. Lack of E-cadherin expression in CLL cells also results in an increase in translocation of β-catenin and upregulation of the Wnt pathway.²⁰

Wnt-target genes include Myc, LEF, cyclinD1, COX-2, and MMP. Gene expression profiling from our laboratory and other groups have identified the overexpression of these wnt-target genes and support this pathway activation in CLL cells.²⁰ This is a promising signalling pathway and an active area of research for developing inhibitors that will have a growth inhibitory effect on CLL leukemic cells. GSK3b inhibitors and other drugs that re-express epigenetically silenced Wnt antagonist genes have been shown to inhibit this pathway activity in CLL cells in vitro.

Notch Pathway Activation

High-throughput exome sequencing has identified recurring mutations in a number of genes, including NOTCH1.²¹ Analysis of additional CLL patients confirmed activating NOTCH1 mutations in 10% to 15% of CLL patients and were also associated with poor outcome.²² This pathway is activated by ligands such as Jagged and Delta-like, which interact with the Notch receptor, which is then cleaved by γ-secretases. The cleaved intracellular domain of the NOTCH1 receptor in combination with other factors activates transcription of target genes, including Myc and HES1 (Figure). Besides the mutations that generate a truncated protein or may stabilize the pathway, the Notch pathway is also constitutively active in CLL specimens.²³ Notch stimulation increases activity of prosurvival pathways and genes such as NFκB that resist apoptotic signals. The pathway can be inhibited by γ-secretase inhibitors (GSIs), which reduce the levels of cleaved NOTCH1 protein and downregulated Notch target genes. This pathway is also able to modulate the microenvironment stimuli as the GSIs inhibit responses to chemokines such as CXCL12 and inhibit migration and invasion.²⁴

Newer Theraputic Agents

Work on signaling mechanisms paid dividends in CLL with the recent development of 2 inhibitors. Ibrutinib (BTK inhibitor) and idelalisib (PI3K inhibitor) are being studied in clinical trials, and both drugs block the BCR and microenvironment signaling pathways, thereby inhibiting the growth of CLL cells.

BTK Inhibitor: Ibrutinib

The activity of BTK is critical for a number of CLL signaling pathways, and it is a component of the initial signaling complex or signalosome that is formed with BCR signaling. Studies have shown that inhibiting this kinase blocks a number of pathways, including ERK, NFκB, and others. The drug ibrutinib blocks this kinase by forming a covalent bond and inhibiting its enzyme activity. This orally bioavailable drug showed activity in phase 1 trials in different B-cell malignancies.²⁵ In a phase 2 study, high-risk CLL patients were given 2 different doses of this inhibitor, and the overall response rate was 71% with an overall survival at 26 months of 83%.¹¹ Responses were seen in all patients irrespective of clinical and genetic risk factors. Based on these findings, the drug was approved for clinical use in patients with relapsed or refractory disease. Recently, there are data on the use of this drug as frontline therapy in elderly patients, and the drug was well tolerated.²⁶ There are additional ongoing trials to compare this drug with other agents, including chlorambucil (in chemotherapy-naïve patients) and ofatumumab (in relapsed or refractory patients).

PI3 Kinase p110 Delta Inhibitor: Idelalisib

The crucial finding for the development of this inhibitor was the over-expression of the delta isoform of PI3K p110 in B-cell malignancies.¹⁴ The drug CAL-101 selectively inhibits this constitutively active isoform and induces apoptosis in a number of B-cell malignancies.^15,27 In the phase 1 trial, this inhibitor was evaluated in relapsed/refractory patients at multiple dose levels.²⁸ There was inhibition of PI3K signaling with an overall response rate of 72%, and a partial response rate of 39% was observed in CLL patients. This was followed by a randomized, placebo-controlled phase 3 study in which patients with myelosuppression, decreased renal function, or other illnesses were treated with either rituximab alone or with rituximab and idelalisib.²⁹

At the time of reporting, the median progression-free survival (PFS) was 5.5 months in the placebo arm and was not reached in the idelalisib arm. Overall response rates were higher in the idelalisib group (81% vs 13%) with similar toxicity profiles in the 2 groups. This drug is now being extensively studied in combination with bendamustine and other anti-CD20 antibodies in clinical trials.

A unique toxicity observed with both these inhibitors is the initial lymphocytosis. In the case of ibrutinib, this was seen in a majority of patients (77%) and at the same time there was a response in the nodal disease, implying a redistribution of leukemic cells from the tissues to the peripheral blood.³⁰

A potential explanation is that these drugs inhibit signaling via chemokines and other components of the microenvironment and by inhibiting the homing signals, allows leukemic cells to move out of their niche areas. This was analyzed in a recent study that compared clinical and biochemical parameters of patients who had a complete or partial response with ibrutinib compared with a “partial response except for lymphocytosis.”³⁰ Patients with “partial response except for lymphocytosis” were found to have favorable prognostic factors, and the persisting leukemic cells were not clonally different from the original cells. The progression free survival of patients with “partial response except for lymphocytosis” was also similar to the subgroup with no prolonged lymphocytosis.

Discussion

Several therapeutic agents with novel mechanisms of action are effective in killing the CLL leukemic cells, and a number of targeted agents are currently in the pipeline. The next challenge for treating CLL will be the proper integration of these novel targeted agents with the traditional chemotherapy and chemoimmunotherapy approaches. Let us consider CLL patients in different clinical settings. First, a patient aged 60 years who is otherwise healthy will be treated with possibly all the available chemotherapy and chemoimmunotherapy options, as well as the newer targeted agents. In this clinical setting sequencing of therapy is not a major concern. On the other hand, a patient aged 70 years who is already refractory to multiple lines of therapy is a good candidate for these newer drugs.

The more controversial use of these targeted agents will be in an older patient with some comorbidities and newly diagnosed CLL. In this clinical setting, should one go with traditional chemotherapy/chemoimmunotherapy approaches or consider newer targeted agents? These issues are now being addressed in clinical trials, and with acceptable toxicity profiles these newer drugs will move to the frontline setting.  

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations­–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.