Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs... more Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs have been considered neoplastic disorders that have a propensity to transform to acute leukemia or myelodysplastic syndrome. One of the MPDs, chronic myeloid leukemia (CML), has the distinct cytogenetic abnormality of the Philadelphia chromosome. In CML, transformation to acute leukemia is a common occurrence, with the timeline measured in years rather than decades. With the other three disorders from this group, polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF), transformation to acute leukemia is less frequently seen and, although variable, can take a longer period of time. The choice of therapy used for MPDs may contribute to leukemic transformation; chlorambucil, busulfan, and radiophosphorus are all examples of therapy that have been shown to be leukemogenic. Several studies have suggested the potential leukemogenicity of hydroxyurea (HU), b...
Myelofibrosis with myeloid metaplasia, also known as idiopathic myelofibrosis (IF) or agnogenic m... more Myelofibrosis with myeloid metaplasia, also known as idiopathic myelofibrosis (IF) or agnogenic myeloid metaplasia, is one of the characteristic manifestations of polycythemia vera (PV) in the spent phase, and has a particularly adverse prognosis. IF may also present de novo. To date, treatment strategies for both spent-phase PV and IF have frustrated both clinicians and patients, with little clear progress made over the past 50 years. Treatment modalities with some benefit in chronic myeloid leukemia (CML), such as interferon (IFN), have been used to shrink the massive organomegaly seen in these patients and to improve their marrow function, but are not curative, and not all patients respond or can tolerate the agent. A curative approach is allogeneic peripheral hematopoietic stem cell transplantation. The preparative regimens used in fully ablative techniques rule out older patients for consideration, and many younger patients with good prognostic criteria may do sufficiently well on medical treatment or observation to avoid transplantation. Older patients may have the option to undergo a human leukocyte antigen (HLA)-identical sibling transplant using a reduced intensity preparative regimen in order to minimize peritransplant mortality. Thus a prerequisite to the broad use of transplantation is objective determination of candidacy. Several evaluation methods agree that anemia, age, and cytogenetic abnormalities all predict poor survival in IF, suggesting that patients with anemia and an abnormal karyotype are the prime candidates for allogeneic transplantation. Experimental peripheral blood models that may reflect the degree of marrow fibrosis, such as the serum procollagen 3 peptide assay, have been used to determine if they are more informative of patient status than a single, random bone marrow sampling. Marrow fibrosis may be patchy, and thus a marrow biopsy alone without other data about marrow function may be misleading. Considerable long-term success in eradicating fibrosis and restoring normal cytogenetics, normal bone marrow morphology, and normal complete blood cell counts through transplantation has been reported. Many questions remain to be answered, however, before the appropriate role of hematopoietic stem cell transplantation in the setting of both spent-phase PV and IF can be determined.
The Mount Sinai journal of medicine, New York, 2003
Historically, a variety of hematological disorders of the bone marrow, such as acute leukemia, ch... more Historically, a variety of hematological disorders of the bone marrow, such as acute leukemia, chronic myelocytic leukemia and severe aplastic anemia, were invariably fatal. In the past two decades, basic and clinical scientists have been able to change this grim reality into a more hopeful outcome by replacing the diseased bone marrow with stem cells from either a family donor or an unrelated volunteer donor with identical human leukocyte antigens (HLA). Because of progress in this field, the initial experience of mainly using sibling donors has now been expanded to the use of either unrelated adult donors or cord blood cells as a source of hematopoietic cells. These approaches have created ethical concerns for donors and families, concerns that need to be discussed and understood by patients, volunteer donors and health care professionals.
Hydroxyurea (HU) is an effective therapeutic agent for patients with myeloproliferative disorders... more Hydroxyurea (HU) is an effective therapeutic agent for patients with myeloproliferative disorders (MPDs) or sickle cell disease (SCD). Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been associated with an increased risk of leukemia in some patients with MPD. In this study, 2 assays were used to quantitate acquired somatic DNA mutations in peripheral blood mononuclear cells (PBMCs) after in vivo HU exposure. The HPRT assay measures hypoxanthine phosphoribosyl transferase (hprt) mutations, while the VDJ assay identifies "illegitimate" T-cell receptor Vgamma-Jbeta interlocus recombination events. PBMCs were analyzed from patients with MPD, adults and children with SCD, and normal controls. MPD patients with prolonged HU exposure had numbers of DNA mutations equivalent to patients with low HU exposure or controls. Similarly, ...
Journal of the American College of Cardiology, 1986
Known variously as disseminated intravascular coagulation, defibrination consumption coagulopathy... more Known variously as disseminated intravascular coagulation, defibrination consumption coagulopathy or, more simply, as defibrination, disseminated intravascular coagulation is a serious epiphenomenon that occurs most often as a complicating factor of an underlying disease process. Although frequently triggered by underlying disease such as infection or tumor, if not recognized and treated appropriately, disseminated intravascular coagulation alone may lead to the patient's death as a result of hemorrhage or thrombosis, or both, of vital organs. Frequently, it may only manifest itself as an abnormality of coagulation tests, causing no immediate problem for the patient, and potentially normalizing when the inciting cause is appropriately managed. The central process that marks disseminated intravascular coagulation is the generation of thrombin in the circulating blood by means of the activation of the coagulation mechanism, leading to the conversion of fibrinogen to fibrin, which,...
Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder... more Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder (MPD) is surrounded by controversy. Although few doubt the association of thrombocytosis with increased risk for life-threatening events such as thrombosis or hemorrhage, or the association between clonal myeloproliferation and the progression to acute leukemia or myelofibrosis, controversy exists regarding the timing and nature of appropriate therapeutic intervention. Studies have shown that treatment with myelosuppressive agents such as chlorambucil, busulfan, radiophosphorus (32P), and hydroxyurea reduces the platelet count. However, investigators have also identified an increased risk of drug-related leukemic transformation. An ideal cytoreductive treatment for long-term use should minimize thrombosis and avoid long-term complications, especially acute leukemia (AL). Anagrelide, an imidazoquinolin, inhibits megakaryopoiesis and more selectively reduces platelet production in humans. A retrospective analysis of an open-label, multicenter, international trial reviewing 3660 anagrelide-treated patients was performed to assess efficacy and long-term safety, specifically potential for increased leukemogenicity. The study included MPD patients with thrombocytosis diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of all patients enrolled, 81% had previously received other myelosuppressive agents; of these, 33% were transferred from the original agent to anagrelide due to toxicity and 31% were transferred because of poor platelet control. Over 45% of patients were symptomatic due to thrombocythemia, most commonly vascular sequelae (25%). Dosage was titrated to achieve a platelet count < 600 x 10(9) L(-1) and ideally between 130 and 450 x 10(9) L(-1). The safety cohort of 3660 patients, including 2251 with essential thrombocythemia (ET), 462 with polycythemia vera (PV), and 947 with chronic myeloid leukemia (CML) and other MPDs, was analyzed to establish the incidence of leukemic transformation in patients with ET and PV. From the Safety Population, 12.8% (467/3660) of patients were treated with anagrelide as the sole cytoreductive agent (naive patients). Acute leukemia/myelodysplasia developed in 2.1% of ET patients (47/2251) with a maximum follow-up of 7.1 years. Of the PV patients, 2.8% developed acute leukemia/myelodysplastic syndrome (13/462), with a maximum follow-up of 7.0 years. ET and PV patients who transformed to AL had all been previously exposed to other cytotoxics; there were no ET or PV patients in the study who transformed to AL exposed solely to anagrelide. With maximum follow-up over 7 years, anagrelide achieved platelet control in over 75% of MPD patients and did not increase the conversion to acute leukemia during the treatment duration analyzed. Longer follow-up is required to confirm these important observations regarding the long-term safety of anagrelide.
This report describes a new familial syndrome characterized by a combination of bone marrow failu... more This report describes a new familial syndrome characterized by a combination of bone marrow failure and chronic liver disease. This disorder appears to be genetic in origin with an autosomal dominant inheritance and was characterized by hyperactivity of the immune system with increased activated cytotoxic T lymphocytes in peripheral blood and bone marrow and the presence of gamma-interferon messenger RNA in bone marrow of several cases.
Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pa... more Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 an...
A total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 ... more A total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 years (range, 27-68 years), were prepared with a reduced-intensity conditioning (RIC) regimen. The patients received an allogeneic marrow (n = 3) or peripheral blood stem-cell (n = 18) transplant from HLA-matched related (n = 18) or unrelated (n = 2), or 1 Ag-mismatched related (n = 1), donors. RIC regimens included fludarabine/total body irradiation 200 cGy (n = 5) or 450 cGy (n = 1), fludarabine/melphalan (n = 7), thiotepa/cyclophosphamide (n = 7), and thiotepa/fludarabine (n = 1). At the time of transplantation, all of the patients were at intermediate (n = 13) or high (n = 8) risk, according to the Dupriez classification. Of the patients, 19 had grade III or IV marrow fibrosis. All of the patients achieved full engraftment but one. Posttransplantation chimerism analysis showed more than 95% donor cells in 18 patients, while 2 patients achieved complete donor chimerism after donor leu...
Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs... more Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs have been considered neoplastic disorders that have a propensity to transform to acute leukemia or myelodysplastic syndrome. One of the MPDs, chronic myeloid leukemia (CML), has the distinct cytogenetic abnormality of the Philadelphia chromosome. In CML, transformation to acute leukemia is a common occurrence, with the timeline measured in years rather than decades. With the other three disorders from this group, polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF), transformation to acute leukemia is less frequently seen and, although variable, can take a longer period of time. The choice of therapy used for MPDs may contribute to leukemic transformation; chlorambucil, busulfan, and radiophosphorus are all examples of therapy that have been shown to be leukemogenic. Several studies have suggested the potential leukemogenicity of hydroxyurea (HU), b...
Myelofibrosis with myeloid metaplasia, also known as idiopathic myelofibrosis (IF) or agnogenic m... more Myelofibrosis with myeloid metaplasia, also known as idiopathic myelofibrosis (IF) or agnogenic myeloid metaplasia, is one of the characteristic manifestations of polycythemia vera (PV) in the spent phase, and has a particularly adverse prognosis. IF may also present de novo. To date, treatment strategies for both spent-phase PV and IF have frustrated both clinicians and patients, with little clear progress made over the past 50 years. Treatment modalities with some benefit in chronic myeloid leukemia (CML), such as interferon (IFN), have been used to shrink the massive organomegaly seen in these patients and to improve their marrow function, but are not curative, and not all patients respond or can tolerate the agent. A curative approach is allogeneic peripheral hematopoietic stem cell transplantation. The preparative regimens used in fully ablative techniques rule out older patients for consideration, and many younger patients with good prognostic criteria may do sufficiently well on medical treatment or observation to avoid transplantation. Older patients may have the option to undergo a human leukocyte antigen (HLA)-identical sibling transplant using a reduced intensity preparative regimen in order to minimize peritransplant mortality. Thus a prerequisite to the broad use of transplantation is objective determination of candidacy. Several evaluation methods agree that anemia, age, and cytogenetic abnormalities all predict poor survival in IF, suggesting that patients with anemia and an abnormal karyotype are the prime candidates for allogeneic transplantation. Experimental peripheral blood models that may reflect the degree of marrow fibrosis, such as the serum procollagen 3 peptide assay, have been used to determine if they are more informative of patient status than a single, random bone marrow sampling. Marrow fibrosis may be patchy, and thus a marrow biopsy alone without other data about marrow function may be misleading. Considerable long-term success in eradicating fibrosis and restoring normal cytogenetics, normal bone marrow morphology, and normal complete blood cell counts through transplantation has been reported. Many questions remain to be answered, however, before the appropriate role of hematopoietic stem cell transplantation in the setting of both spent-phase PV and IF can be determined.
The Mount Sinai journal of medicine, New York, 2003
Historically, a variety of hematological disorders of the bone marrow, such as acute leukemia, ch... more Historically, a variety of hematological disorders of the bone marrow, such as acute leukemia, chronic myelocytic leukemia and severe aplastic anemia, were invariably fatal. In the past two decades, basic and clinical scientists have been able to change this grim reality into a more hopeful outcome by replacing the diseased bone marrow with stem cells from either a family donor or an unrelated volunteer donor with identical human leukocyte antigens (HLA). Because of progress in this field, the initial experience of mainly using sibling donors has now been expanded to the use of either unrelated adult donors or cord blood cells as a source of hematopoietic cells. These approaches have created ethical concerns for donors and families, concerns that need to be discussed and understood by patients, volunteer donors and health care professionals.
Hydroxyurea (HU) is an effective therapeutic agent for patients with myeloproliferative disorders... more Hydroxyurea (HU) is an effective therapeutic agent for patients with myeloproliferative disorders (MPDs) or sickle cell disease (SCD). Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been associated with an increased risk of leukemia in some patients with MPD. In this study, 2 assays were used to quantitate acquired somatic DNA mutations in peripheral blood mononuclear cells (PBMCs) after in vivo HU exposure. The HPRT assay measures hypoxanthine phosphoribosyl transferase (hprt) mutations, while the VDJ assay identifies "illegitimate" T-cell receptor Vgamma-Jbeta interlocus recombination events. PBMCs were analyzed from patients with MPD, adults and children with SCD, and normal controls. MPD patients with prolonged HU exposure had numbers of DNA mutations equivalent to patients with low HU exposure or controls. Similarly, ...
Journal of the American College of Cardiology, 1986
Known variously as disseminated intravascular coagulation, defibrination consumption coagulopathy... more Known variously as disseminated intravascular coagulation, defibrination consumption coagulopathy or, more simply, as defibrination, disseminated intravascular coagulation is a serious epiphenomenon that occurs most often as a complicating factor of an underlying disease process. Although frequently triggered by underlying disease such as infection or tumor, if not recognized and treated appropriately, disseminated intravascular coagulation alone may lead to the patient's death as a result of hemorrhage or thrombosis, or both, of vital organs. Frequently, it may only manifest itself as an abnormality of coagulation tests, causing no immediate problem for the patient, and potentially normalizing when the inciting cause is appropriately managed. The central process that marks disseminated intravascular coagulation is the generation of thrombin in the circulating blood by means of the activation of the coagulation mechanism, leading to the conversion of fibrinogen to fibrin, which,...
Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder... more Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder (MPD) is surrounded by controversy. Although few doubt the association of thrombocytosis with increased risk for life-threatening events such as thrombosis or hemorrhage, or the association between clonal myeloproliferation and the progression to acute leukemia or myelofibrosis, controversy exists regarding the timing and nature of appropriate therapeutic intervention. Studies have shown that treatment with myelosuppressive agents such as chlorambucil, busulfan, radiophosphorus (32P), and hydroxyurea reduces the platelet count. However, investigators have also identified an increased risk of drug-related leukemic transformation. An ideal cytoreductive treatment for long-term use should minimize thrombosis and avoid long-term complications, especially acute leukemia (AL). Anagrelide, an imidazoquinolin, inhibits megakaryopoiesis and more selectively reduces platelet production in humans. A retrospective analysis of an open-label, multicenter, international trial reviewing 3660 anagrelide-treated patients was performed to assess efficacy and long-term safety, specifically potential for increased leukemogenicity. The study included MPD patients with thrombocytosis diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of all patients enrolled, 81% had previously received other myelosuppressive agents; of these, 33% were transferred from the original agent to anagrelide due to toxicity and 31% were transferred because of poor platelet control. Over 45% of patients were symptomatic due to thrombocythemia, most commonly vascular sequelae (25%). Dosage was titrated to achieve a platelet count < 600 x 10(9) L(-1) and ideally between 130 and 450 x 10(9) L(-1). The safety cohort of 3660 patients, including 2251 with essential thrombocythemia (ET), 462 with polycythemia vera (PV), and 947 with chronic myeloid leukemia (CML) and other MPDs, was analyzed to establish the incidence of leukemic transformation in patients with ET and PV. From the Safety Population, 12.8% (467/3660) of patients were treated with anagrelide as the sole cytoreductive agent (naive patients). Acute leukemia/myelodysplasia developed in 2.1% of ET patients (47/2251) with a maximum follow-up of 7.1 years. Of the PV patients, 2.8% developed acute leukemia/myelodysplastic syndrome (13/462), with a maximum follow-up of 7.0 years. ET and PV patients who transformed to AL had all been previously exposed to other cytotoxics; there were no ET or PV patients in the study who transformed to AL exposed solely to anagrelide. With maximum follow-up over 7 years, anagrelide achieved platelet control in over 75% of MPD patients and did not increase the conversion to acute leukemia during the treatment duration analyzed. Longer follow-up is required to confirm these important observations regarding the long-term safety of anagrelide.
This report describes a new familial syndrome characterized by a combination of bone marrow failu... more This report describes a new familial syndrome characterized by a combination of bone marrow failure and chronic liver disease. This disorder appears to be genetic in origin with an autosomal dominant inheritance and was characterized by hyperactivity of the immune system with increased activated cytotoxic T lymphocytes in peripheral blood and bone marrow and the presence of gamma-interferon messenger RNA in bone marrow of several cases.
Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pa... more Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 an...
A total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 ... more A total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 years (range, 27-68 years), were prepared with a reduced-intensity conditioning (RIC) regimen. The patients received an allogeneic marrow (n = 3) or peripheral blood stem-cell (n = 18) transplant from HLA-matched related (n = 18) or unrelated (n = 2), or 1 Ag-mismatched related (n = 1), donors. RIC regimens included fludarabine/total body irradiation 200 cGy (n = 5) or 450 cGy (n = 1), fludarabine/melphalan (n = 7), thiotepa/cyclophosphamide (n = 7), and thiotepa/fludarabine (n = 1). At the time of transplantation, all of the patients were at intermediate (n = 13) or high (n = 8) risk, according to the Dupriez classification. Of the patients, 19 had grade III or IV marrow fibrosis. All of the patients achieved full engraftment but one. Posttransplantation chimerism analysis showed more than 95% donor cells in 18 patients, while 2 patients achieved complete donor chimerism after donor leu...
Uploads
Papers by Steven Fruchtman