Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, antithymocyte globulin, and methotrexate before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well sirolimus, tacrolimus, and antithymocyte globulin work in preventing graft-versus-host disease in patients undergoing a donor stem cell transplant for hematological cancer .

Detailed Description
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OBJECTIVES: Primary To determine the incidence and severity of acute- and chronic-graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor hematopoietic peripheral blood transplantation in patients with hematologic malignancies scheduled to receive immunosuppressive combination of sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis. To determine the safety of this combination in the first six months post-transplant. Secondary To determine the time-to-engraftment, non-relapse mortality rate, overall and disease-free survival, incidence of disease relapse, and incidence of opportunistic infections with this GVHD prophylaxis. OUTLINE: Patients are stratified according to conditioning regimen (fludarabine phosphate and melphalan vs fractionated total-body irradiation [FTBI] and etoposide vs FTBI and cyclophosphamide) and degree of donor/recipient HLA mismatch (high-risk vs low-risk). Conditioning regimen: Patients receive 1 of 3 standard conditioning regimens beginning on day -9 or -8 and continuing to day -1 or 0. Peripheral blood stem cell transplantation: Patients receive HLA-matched or mismatched unrelated donor peripheral blood stem cells on day 0. Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -3 and then orally when tolerated, oral sirolimus on days -3 and -2, anti-thymocyte globulin IV over 4-8 hours on days -3 to 0, and methotrexate* IV on days 1, 3, and 6. Tacrolimus and sirolimus continue for 3-6 months (with taper). NOTE: *Only patients with high-risk HLA mismatch receive treatment with methotrexate. After completion of study therapy, patients are followed periodically for up to 2 years.

Official Title
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A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin, as Graft-versus-Host Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

Conditions
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Chronic Myeloproliferative Disorders, Graft Versus Host Disease, Infection, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Precancerous Condition, Secondary Myelofibrosis, Small Intestine Cancer

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: cyclophosphamide
* Drug: etoposide
* Drug: fludarabine phosphate
* Drug: melphalan
* Drug: methotrexate
* Drug: sirolimus
* Drug: tacrolimus
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: hematopoietic stem cell transplantation
* Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of hematological malignancy including any of the following: Non-Hodgkin lymphoma (NHL) in any complete remission (CR) or partial response (PR) Hodgkin lymphoma in any CR or PR Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in any CR Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation of conditioning for patients with non-CR AML or ALL Myelodysplastic syndromes (MDS) treated or untreated Chronic myelogenous leukemia (CML) in chronic or accelerated phase Multiple myeloma in any CR or PR Chronic lymphocytic leukemia in CR or PR 2 or greater Myelofibrosis and other myeloproliferative disorders Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation High-risk disease defined as AML or ALL > CR1, accelerated phase CML, recurrent aggressive lymphoma, or active lymphoproliferative disease at transplant Low-risk disease defined as AML or ALL in CR1, chronic phase CML, or low-grade lymphoproliferative disorder with controlled disease at transplant Must be planning to receive 1 of the following conditioning regimens at City of Hope: Fludarabine phosphate and melphalan for patients with hematological malignancies and contraindications for conventional myeloablative regimens due to age, co-morbidity, or previous transplant Fractionated total-body irradiation (FTBI) and etoposide for patients with AML and ALL or CML in accelerated phase FTBI and cyclophosphamide for patients with NHL, AML, CML, and MDS Suitable unrelated donor available HLA-matched or mismatched Peripheral blood stem cells available No bone marrow or ex vivo-engineered or processed graft (e.g., CD34-positive, T-cell depletion) No uncontrolled CNS disease PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 70-100% or ECOG PS 0-2 Creatinine < 1.3 mg/dL or creatinine clearance ≥ 70 mL/min Ejection fraction > 45% Direct bilirubin < 3 times upper limit of normal (ULN) ALT and AST < 3 times ULN Forced vital capacity, FEV1, and DLCO > 45% of predicted Able to cooperate with oral medication intake No active donor or recipient serology positive for HIV No known contraindication to administration of sirolimus, tacrolimus, or anti-thymocyte globulin No active hepatitis B or C Negative pregnancy test PRIOR CONCURRENT THERAPY: See Disease Characteristics Concurrent participation in other clinical trials for prevention or treatment of viral, bacterial, or fungal disease allowed provided agents do not interact with agents used in the current study

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine/Melphalan Conditioning<br>Fludarabine/Melphalan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis | Biological: anti-thymocyte globulin<br>* 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant<br>Drug: fludarabine phosphate<br>* Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant<br>Drug: melphalan<br>* Melphalan 140 mg/m2 on day -4 from stem cell transplant<br>Drug: methotrexate<br>* For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant<br>Drug: sirolimus<br>* Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose<br>Drug: tacrolimus<br>* 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation<br>* Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant<br>Procedure: peripheral blood stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Radiation: total-body irradiation<br>* 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant<br>|
| Experimental: FTBI/Cytoxan Conditioning<br>FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis | Biological: anti-thymocyte globulin<br>* 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant<br>Drug: cyclophosphamide<br>* 60mg/kg on days -5 and -4 from stem cell transplant<br>Drug: methotrexate<br>* For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant<br>Drug: sirolimus<br>* Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose<br>Drug: tacrolimus<br>* 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation<br>* Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant<br>Procedure: peripheral blood stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Radiation: total-body irradiation<br>* 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant<br>|
| Experimental: FTBI/Etoposide Conditioning<br>FTBI/Etoposide Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis | Biological: anti-thymocyte globulin<br>* 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant<br>Drug: etoposide<br>* 60mg/kg on day -4 from stem cell transplant<br>Drug: methotrexate<br>* For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant<br>Drug: sirolimus<br>* Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose<br>Drug: tacrolimus<br>* 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: hematopoietic stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation<br>* Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant<br>Procedure: peripheral blood stem cell transplantation<br>* The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight<br>Radiation: total-body irradiation<br>* 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100 | Patients were evaluated for the development of acute GVHD within the first 100 days post HSCT. The cumulative incidence of grade II-IV acute GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death and nonengraftment. | 100 Days Post Hematopoietic Stem Cell Transplant (HSCT) | 
| Severity of Acute GVHD | All patients were considered for the evaluation of the severity of acute GVHD. | 100 Days Post HSCT | 
| Cumulative Incidence of Chronic GVHD | Patients were evaluated for the development of chronic GVHD from 101 days post HSCT to last contact or documented evidence of the disease. The cumulative incidence of chronic GVHD was determined using competing risk analysis. Competing risks for GVHD were death and nonengraftment. | 2 year point estimate was provided. | 
| Severity of Chronic GVHD | All Patients were considered for the evaluation of chronic GVHD severity. | Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Absolute Neutrophil Count Recovery (Engraftment) | Absolute neutrophil count (ANC) recovery is defined as an ANC of ≥ 0.5 x 10^9/L (500/mm3) for three consecutive laboratory values obtained on different days | Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT | 
| Time to Platelet Count Recovery (Engraftment) | Platelet recovery is defined as the first date of three consecutive laboratory values ≥ 25 x 10^9 L obtained on different days. | Patients were evaluated until platelet recovery, a median of 14 days | 
| Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation | Participants were monitored throughout the trial (median of 28 months) for various infections/complications. | Median Follow Up: 28 months (Range: 1-49 months) | 
| Occurrence of Thrombotic Microangiopathy | Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed TMA. | Median Follow Up: 28 Months (Range: 1-49 months) | 
| Occurence of Sinusoidal Obstructive Syndrome (SOS) | Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed SOS. | Median Follow Up: 28 Months (Range: 1-49 Months) | 
| Non-relapse Mortality at 100 Days Post HSCT | Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment. | 100 day point estimate was provided | 
| Non-relapse Mortality at Two Years Post HSCT | Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment. | 2 year point estimate was provided. | 
| Overall Survival at Two Years Post HSCT | Patients were evaluated for survival (OS) throughout the study. Kaplan Meier estiamtes were calculated for overall survival using time from HSCT to death of any cause or for surviving patients last contact date. | 2 year point estimate was provided. | 
| Event Free Survival at Two Years Post HSCT | Patients were evaluated for event free survival (EFS) throughout the study. Events were defined as death, relapse, progression, or nonengraftment. Kaplan Meier estimates were calculated as time from HSCT to event. | 2 year point estimate was provided. | 
| Incidence of Disease Relapse/Progression at 2 Years Post HSCT | Patients were evaluated for relapse/progression post transplant throughout the study. The cumulative incidence of relapse/progression was determined using competing risk analysis. Competing risks for relapse were non-relapse mortality and nonengraftment. | 2 year point estimate was provided. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Burkitt lymphoma, graft versus host disease, infection, adult favorable prognosis Hodgkin lymphoma, adult unfavorable prognosis Hodgkin lymphoma, childhood favorable prognosis Hodgkin lymphoma, childhood unfavorable prognosis Hodgkin lymphoma, cutaneous B-cell non-Hodgkin lymphoma, recurrent adult Hodgkin lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent/refractory childhood Hodgkin lymphoma, stage I adult Hodgkin lymphoma, stage I childhood Hodgkin lymphoma, stage I cutaneous T-cell non-Hodgkin lymphoma, stage II adult Hodgkin lymphoma, stage II childhood Hodgkin lymphoma, stage II cutaneous T-cell non-Hodgkin lymphoma, stage III adult Hodgkin lymphoma, stage III childhood Hodgkin lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage IV childhood Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, contiguous stage II adult Burkitt lymphoma, contiguous stage II adult diffuse large cell lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, contiguous stage II adult diffuse small cleaved cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, contiguous stage II adult lymphoblastic lymphoma, contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, contiguous stage II mantle cell lymphoma, contiguous stage II marginal zone lymphoma, contiguous stage II small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent childhood anaplastic large cell lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent grade I lymphomatoid granulomatosis, recurrent grade II lymphomatoid granulomatosis, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, small intestine lymphoma, splenic marginal zone lymphoma, stage I adult Burkitt lymphoma, stage I adult diffuse large cell lymphoma, stage I adult diffuse mixed cell lymphoma, stage I adult diffuse small cleaved cell lymphoma, stage I adult immunoblastic large cell lymphoma, stage I adult lymphoblastic lymphoma, stage I adult T-cell leukemia/lymphoma, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III adult T-cell leukemia/lymphoma, stage III childhood anaplastic large cell lymphoma, stage III childhood lymphoblastic lymphoma, stage III childhood small noncleaved cell lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV adult T-cell leukemia/lymphoma, stage IV childhood anaplastic large cell lymphoma, stage IV childhood lymphoblastic lymphoma, stage IV childhood small noncleaved cell lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV small lymphocytic lymphoma, adult acute myeloid leukemia in remission, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), childhood acute myeloid leukemia in remission, recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, adult acute lymphoblastic leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, accelerated phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, refractory chronic lymphocytic leukemia, relapsing chronic myelogenous leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, childhood myelodysplastic syndromes, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL negative, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, primary myelofibrosis, secondary myelofibrosis