PRIMARY OBJECTIVES:
I. Compare chronic graft versus host disease (GVHD)-free and relapse-free survival (CRFS)
after transplant between the 2 GVHD prophylaxis regimens.
SECONDARY OBJECTIVES:
I. Compare rates of acute (grades II-IV and III-IV) and moderate and severe chronic GVHD
(based on National Institutes of Health [NIH] consensus criteria), relapse, non-relapse
mortality, progression or relapse-free survival, and overall survival between the 2 regimens.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo allogeneic hematopoietic stem cell transplant (HCT) at day 0.
Patients with an HLA-matched unrelated donor receive mycophenolate mofetil orally (PO) on
days 0 to 40, cyclosporine PO every 12 hours twice daily (BID) on days -3 to 96 then tapered
to day 150, and sirolimus PO once daily (QD) on days -3 to day 150 then tapered to day 180.
Patients with an HLA-mismatched donor receive mycophenolate mofetil PO on days 0-100 then
tapered to day 150, cyclosporine PO BID on days -3 to 150 then tapered to day 180, and
sirolimus PO QD on days -3 to 180 then tapered to day 365.
ARM II: Patients undergo HCT at day 0. Patients with an HLA-matched unrelated donor receive
cyclosporine PO BID on days 5-96 then tapered to day 150, sirolimus PO QD on days 5-150 then
tapered to day 180, and cyclophosphamide intravenously (IV) on days 3 and 4. Patients with an
HLA-mismatched donor receive cyclosporine PO BID on days 5-150 then tapered to day 180,
sirolimus PO QD on days 5-180 then tapered to day 365, and cyclophosphamide IV on days 3 and
4.
After completion of study treatment, patients are followed up at 6 months and every year
thereafter.
Inclusion Criteria:
- Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic
cell transplant (HCT)
- Ages 18-50 years with hematologic diseases treatable by allogeneic HCT who through
pre-existing medical conditions or prior therapy are considered to be at high risk for
regimen related toxicity associated with a high dose transplant (> 40% risk of
transplant related mortality [TRM]); this criterion can include patients with a
hematopoietic cell transplant-comorbidity index (HCT-CI) score of > 3; transplants
should be approved for these inclusion criteria by the principal investigators at the
collaborating centers and at Fred Hutchinson Cancer Research Center (FHCRC)
- Ages 18-50 years with chronic lymphocytic leukemia (CLL)
- Ages 18-50 years with hematologic diseases treatable by allogeneic HCT who refuse a
high-dose HCT; transplants must be approved for these inclusion criteria by the
principal investigators at the collaborating centers and at FHCRC
- Aggressive nonHodgkin lymphomas (NHL) and other histologies such as diffuse large B
cell NHL- not eligible for autologous HCT, not eligible for high-dose allogeneic HCT,
or after failed autologous HCT
- Mantle cell NHL-may be treated in first complete remission (CR); (diagnostic lumbar
puncture [LP] required pre-transplant)
- Low grade NHL - with < 6 month duration of CR between courses of conventional therapy
- CLL - must have either 1) failed to meet National Cancer Institute (NCI) Working Group
criteria for complete or partial response after therapy with a regimen containing
fludarabine (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin)
or experience disease relapse within 12 months after completing therapy with a regimen
containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide
(CY)-rituximab (FCR) combination chemotherapy at any time point; or 3) have "17p
deletion" cytogenetic abnormality; patients should have received induction
chemotherapy but could be transplanted in 1st CR; or 4) patients with a diagnosis of
CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to
prolymphocytic leukemia (PLL), or T-cell CLL or PLL; 5) patients failing to achieve a
response to ibrutinib as first-line therapy; 6) patients not responding to ibrutinib,
idelalisib, or venetoclax as salvage therapy or intolerant of these agents as salvage
therapy due to side effects; all CLL patients must have received prior
myelosuppressive chemotherapy
- Hodgkin lymphoma - must have received and failed frontline therapy
- Multiple myeloma - must have received prior chemotherapy; consolidation of
chemotherapy by autografting prior to nonmyeloablative HCT is permitted
- Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
- Acute lymphocytic leukemia (ALL) - must have < 5% marrow blasts at the time of
transplant
- Chronic myeloid leukemia (CML) - patients in CP1 must have failed or be intolerant of
tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they have <
5% marrow blasts at time of transplant
- Myelodysplasia (MDS)/myeloproliferative syndrome (MPS)/chronic myelomonocytic leukemia
(CMML) - patients must have < 5% marrow blasts at time of transplant
- Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy
- Mixed Phenotype Acute Leukemia (MPAL) - must have < 5% marrow blasts at the time of
transplant.
- Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) - must be in complete remission
at the time of transplant
- HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1;
unrelated donors who are prospectively:
- Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;
- Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing
- HLA-MATCHED UNRELATED DONOR: Donors are excluded when preexisting immunoreactivity is
identified that would jeopardize donor hematopoietic cell engraftment; this
determination is based on the standard practice of the individual institution; the
recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match
is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens
for all patients before HCT; if the PRA shows > 10% activity, then flow cytometric or
B and T cell cytotoxic cross matches should be obtained; the donor should be excluded
if any of the cytotoxic cross match assays are positive; for those patients with an
HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches
should be obtained regardless of the PRA results; a positive anti-donor cytotoxic
crossmatch is an absolute donor exclusion
- HLA-MATCHED UNRELATED DONOR: Patient and donor pairs homozygous at a mismatched allele
in the graft rejection vector are considered a two-allele mismatch, i.e., the patient
is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
- HLA-MATCHED UNRELATED DONOR: Only granulocyte colony-stimulating factor (G-CSF)
mobilized PBSC will be permitted as a HSC source on this protocol
- HLA-MISMATCHED UNRELATED DONOR: Unrelated volunteer donors who are mismatched with the
recipient within one of the following limitations:
- Mismatch for one HLA class I antigen with or without an additional mismatch for
one HLA-class I allele, but matched for HLA-DRB1 and HLA-DQ, OR
- Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ
- HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1
and/or DQB1 antigen/allele mismatch
- HLA-MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high
resolution typing at HLA-A, -B, -C, - DRB1, and -DQ
- HLA-MISMATCHED UNRELATED DONOR: If the patient is homozygous at the mismatch HLA class
I locus or II locus, the donor must be heterozygous at that locus and one allele must
match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous
A*01:01, A*02:01); this mismatch will be considered a one-antigen mismatch for
rejection only
Exclusion Criteria:
- Patients with rapidly progressive intermediate or high grade NHL
- Patients with a diagnosis of chronic myelomonocytic leukemia (CMML) who have not
received induction chemotherapy
- Patients with refractory anemia with excess blasts (RAEB) who have not received
myelosuppressive chemotherapy i.e. induction chemotherapy and will receive
conditioning Regimen B (fludarabine and total body irradiation [TBI]) will be
excluded; patients with RAEB who have not received myelosuppressive chemotherapy but
who will receive conditioning Regimen A are eligible for this study as long as other
inclusion and exclusion criteria are met
- CNS involvement with disease refractory to intrathecal chemotherapy
- Presence of circulating blasts (in the blood) detected by standard pathology for
patients with AML, ALL or CML
- Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard
pathology for patients with MDS/MPS/CMML
- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment
- Females who are pregnant or breast-feeding
- Patients with active non-hematological malignancies (except non-melanoma skin cancers)
or those with non-hematological malignancies (except non-melanoma skin cancers) who
have been rendered with no evidence of disease, but have a greater than 20% chance of
having disease recurrence within 5 years; this exclusion does not apply to patients
with non-hematologic malignancies that do not require therapy
- Fungal infections with radiological progression after receipt of amphotericin B or
active triazole for greater than 1 month
- Organ dysfunction
- Cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction,
shortening fraction of < 26%); ejection fraction is required if age > 50 years or
there is a history of anthracycline exposure or history of cardiac disease;
patients with a shortening fraction < 26% may be enrolled if approved by a
cardiologist
- Pulmonary:
** Diffusing capacity of the lungs for carbon monoxide (DLCO) < 40%, forced
expiratory volume in the first second of breath (FEV1) < 40% and/or receiving
supplementary continuous oxygen; when pulmonary function tests (PFTs) cannot be
obtained, the 6-minute walk test (6MWT, also known as exercise oximetry) will be
used: Any patient with oxygen saturation on room air of < 89% during a 6MWT will
be excluded
- The FHCRC PI of the study must approve of enrollment of all patients with
pulmonary nodules
- Liver function abnormalities: Patients with clinical or laboratory evidence of liver
disease would be evaluated for the cause of liver disease, its clinical severity in
terms of liver function, and the degree of portal hypertension; patients will be
excluded if they are found to have fulminant liver failure, cirrhosis of the liver
with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a
history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic
synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related
to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary
obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or
symptomatic biliary disease
- Karnofsky scores < 60
- Patient has poorly controlled hypertension and on multiple antihypertensives
- Human immunodeficiency virus (HIV) positive patients
- Active bacterial or fungal infections unresponsive to medical therapy
- The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose
cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the
initiation of conditioning
- Patients on hemodialysis
- DONOR: Donor (or centers) who will exclusively donate marrow
- DONOR: Donors who are HIV-positive and/or, medical conditions that would result in
increased risk for G-CSF mobilization and harvest of peripheral blood stem cell (PBSC)
- DONOR: Patients who are homozygous at the mismatched HLA class I or II locus, the
donor is excluded if homozygous at the mismatched locus (i.e., patient is homozygous A
*01:01 and donor is homozygous A *02:01); this type of mismatch is considered a
two-antigen mismatch and is not allowed
