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Collection of sufficient CD34+ cells using plerixafor as the mobilizing agent.

Eligible donors determined according to institutional standards

* 18-65 years of age
* 6/6 HLA-matched sibling
* Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor
* Serum creatinine \<1.5 x institution upper limit of normal (ULN) or estimated creatinine clearance (CLCR) \>50 mL/min

Treatment Description:

* Receive subcutaneous plerixafor at 240 μg/kg and commence leukapheresis approximately 4 hours later.
* Leukapheresis will be performed up to two consecutive days. The target CD34+ cell dose is \> 4.0 x 106/kg with a minimum of \> 2.0 x 106/kg.

Patients undergoing conditioning under a myeloablative regimen

Myeloablative (one of four general regimens):

Busulfan (\> 9 mg/kg po or iv total) with fludarabine Busulfan (\> 9 mg/kg po or iv total) with cyclophosphamide Total body irradiation (\> 1000 cGy) plus etoposide Total body irradiation (\> 500 cGy) plus cyclophosphamide

Patients undergoing conditioning using a reduced intensity conditioning regimen.

Reduced Intensity (one of three general regimens):

Busulfan (\< 9 mg/kg po or iv total) plus fludarabine Melphalan (100-140 mg/m2 iv total) plus fludarabine Fludarabine plus cyclophosphamide (\> 2000 mg/m2 total)

Steve Devine, MD

This is a Phase II, open-label, two strata, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts in recipients with hematological malignancies. This study will establish the safety and efficacy of subcutaneous plerixafor for this purpose.

The primary objective is to determine the proportion of donors whose cells can be successfully mobilized and collected with a sufficient CD34+ cell dose using plerixafor as the mobilizing agent, using an intention-to-treat analysis. Donor mobilization following plerixafor will be considered successful if ≥ 2.0x10e6 CD34+ cells/kg recipient weight are collected in no more than two leukapheresis collections.

All donors receiving plerixafor will be included in the analysis of the primary objective based on the intention-to-treat principle.Recipients will be classified into one of the two strata, myeloablative or reduced intensity, according to his/her conditioning regimen. The target enrollment is 64 donor/recipient pairs, 32 pairs per stratum.

A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor

A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Recipients With Hematological Malignancies

Donor mobilization following plerixafor was considered successful if ≥ 2.0x106 CD34+ cells/kg recipient weight was collected in no more than two leukapheresis collections.

Incidence and severity of acute toxicities before and during apheresis experienced by donors receiving plerixafor. Acute toxicities are graded according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. This outcome measure is descriptive. Grade of maximum toxicity across all time points is reported. Higher grades denote worse outcomes. 0 = None, 1 = Mild, 2 = Moderate, 3 = severe.

Adverse effects experienced by donors receiving plerixafor up to one year post donation. Number of participants with a maximum MTC \>0 reported at each individual time point. Adverse effects are graded according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. This outcome measure is descriptive. Participants can experience adverse effects at more than one time point evaluated. Higher grades denote worse outcomes. 0 = None, 1 = Mild, 2 = Moderate, 3 = severe.

Incidence of and kinetics of neutrophil and platelet recovery by day 100 in recipients after transplantation of hematopoietic cells mobilized with plerixafor.

T-cell (CD3+) and myeloid (CD33+) chimerism in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive.

Incidence of primary graft failure in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive.

Incidence of acute graft-versus-host disease (GVHD) in recipients after transplantation of hematopoietic cells mobilized with plerixafor

Rate and quality of immune reconstitution as evidenced by peripheral blood immunophenotype after transplantation of hematopoietic cells mobilized with plerixafor.

Percentage of recipients with prior CMV infection whose CMV was reactivated after transplantation with cell mobilized with plerixafor

Incidence of treatment-related mortality and disease relapse/progression in recipients after transplantation of hematopoietic cells mobilized with plerixafor

Probability of progression-free and overall survival after transplantation of hematopoietic cells mobilized with plerixafor

Cellular composition of allografts mobilized with plerixafor (stem/progenitor cells, T/B/ (Natural killer) NK-cells)

Incidence of chronic graft-versus-host disease (GVHD) in recipients after transplantation of hematopoietic cells mobilized with plerixafor

Incidence of secondary graft failure in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive.

CD34+ cell count of allografts mobilized with plerixafor

Genzyme, a Sanofi Company

Sanofi

Center for International Blood and Marrow Transplant Research

Recipients were not followed for adverse events.

Collection of sufficient CD34+ cells using plerixafor as the mobilizing agent.

Donor eligibility was determined according to institutional standards Donors met the following criteria:

* 18-65 years of age
* 6/6 HLA-matched sibling
* Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor
* Serum creatinine \<1.5 x institution ULN or estimated creatinine clearance (CLCR) \>50 mL/min

Treatment Description:

* Receive subcutaneous plerixafor at 240 μg/kg and commence leukapheresis approximately 4 hours later.
* Leukapheresis will be performed up to two consecutive days. The target CD34+ cell dose is \> 4.0 x 106/kg with a minimum of \> 2.0 x 106/kg.

Related Donors Receiving Plerixafor

Collection of sufficient CD34+ cells using plerixafor as the mobilizing agent.

Eligible donors determined according to institutional standards

* 18-65 years of age
* 6/6 HLA-matched sibling
* Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor
* Serum creatinine \<1.5 x institution ULN or estimated creatinine clearance (CLCR) \>50 mL/min

Treatment Description:

* Receive subcutaneous plerixafor at 240 μg/kg and commence leukapheresis approximately 4 hours later.
* Leukapheresis will be performed up to two consecutive days. The target CD34+ cell dose is \> 4.0 x 106/kg with a minimum of \> 2.0 x 10E6/kg.

Myeloablative (one of four general regimens):

Busulfan (\> 9 mg/kg po or iv total) with fludarabine Busulfan (\> 9 mg/kg po or iv total) with cyclophosphamide Total body irradiation (\> 1000 cGy) plus etoposide Total body irradiation (\> 500 cGy) plus cyclophosphamide

Recipients, Myeloablative Conditioning Regimen

Reduced Intensity (one of three general regimens):

Busulfan (\< 9 mg/kg po or iv total) plus fludarabine Melphalan (100-140 mg/m2 iv total) plus fludarabine Fludarabine plus cyclophosphamide (\> 2000 mg/m2 total)

Recipients, Reduced Intensity Conditioning Regimen

Total

Age, Categorical

Information collected by subject response to questions on case report forms

Sex: Female, Male

United States

Region of Enrollment

Although this was a prospective multicenter trial, conclusions are limited by the single arm design and small sample size.

Dr. Steven Devine

Percentage of donors mobilized with plerixafor. No comparison group was analyzed.

Recipients were not mobilized with plerixafor.

Percentage of Donors Whose Cells Were Successfully Mobilized and Collected With a Sufficient CD34+ Cell Dose Using Plerixafor as the Mobilizing Agent, Using an Intention-to-treat Analysis.

This is a descriptive analysis. Percentage of donor experiencing toxicities was assessed at 30, 60, 120, and 240 minutes after administration of plerixafor on each day of collection and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.3. Grade of maximum toxicity across all time points is reported.

Max Modified toxicity criteria (MTC) = 0

Max Modified toxicity criteria (MTC) = 1

Max Modified toxicity criteria (MTC) = 2

Max Modified toxicity criteria (MTC) = 3

Collection of sufficient CD34+ cells using plerixafor as the mobilizing agent.

Eligible donors determined according to institutional standards

* 18-65 years of age
* 6/6 HLA-matched sibling
* Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor
* Serum creatinine \<1.5 x institution ULN or estimated creatinine clearance (CLCR) \>50 mL/min

Treatment Description:

* Receive subcutaneous plerixafor at 240 μg/kg and commence leukapheresis approximately 4 hours later.
* Leukapheresis will be performed up to two consecutive days. The target CD34+ cell dose is \> 4.0 x 106/kg with a minimum of \> 2.0 x 106/kg.

Plerixafor

Recipients were not analyzed for this outcome measure

Incidence and Severity of Acute Toxicities

This is a descriptive analysis. The number of donors experiencing toxicities was assessed at 30, 60, 120, and 240 minutes after administration of plerixafor on each day of collection and one, six, and 12 months post-donation. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.3.

30 minutes after administration of plerixafor

60 minutes after administration of plerixafor

120 minutes after administration of plerixafor

240 minutes after administration of plerixafor

One month after administration of plerixafor

Six months after administration of plerixafor

Twelve months after administration of plerixafor

Recipients did not receive plerixafor and were not examined for this outcome.

Adverse Effects

At 100 days after HCT, all patients in both the MAC and the RIC cohorts had achieved neutrophil engraftment. All patients in the MAC arm and 97% of patients in the RIC arm had achieved platelet engraftment. The median time to neutrophil engraftment was 13 and 15 days for MAC and RIC, respectively. The median time to platelet engraftment was 19 and 18 days for MAC and RIC, respectively.

Neutrophil engraftment

Platelet engraftment

Patients were classified to one of the two conditioning regimens - myeloablative (MAC) or reduced intensity conditioning (RIC). A total of 30 MAC and 33 RIC patients were analyzed for this outcome. Neutrophil engraftment was defined as time from day 0 of HCT to the first of 3 consecutive measurements of absolute neutrophil count ≥0.5 × 109/L. Platelet engraftment was defined as the number of days from day 0 of HCT to the first of 3 consecutive values of platelet count ≥20 × 109/L.

Incidence of and Kinetics of Neutrophil and Platelet Recovery After Transplantation of Hematopoietic Cells Mobilized With Plerixafor

Full donor myeloid chimerism was achieved relatively quickly in both RIC and MAC groups (median 100% at day +28 in both RIC and MAC), but conversion to full donor T-cell chimerism appeared to be slower in the RIC patients.

T-cell chimerism for MAC patients: median donor cell % (range):

Day +28: 92(59-100)%, Day +100: 97(76-100)%, Day +180: 100(91-100)%, Day +365: 100(100-100)%

T-cell chimerism for RIC patients: median donor cell % (range):

Day +28: 80(50-100)%, Day +100: 84(64-100)%, Day +180: 95(74-100)%, Day +365: 100(87-100)%

Myeloid chimerism (Day 28)

T-cell chimerism (Day 28)

Myeloid chimerism (Day 100)

T-cell chimerism (Day 100)

Myeloid chimerism (Day 180)

T-cell chimerism (Day 180)

Myeloid chimerism (Day 365)

T-cell chimerism (Day 365)

T-cell (CD3+) and Myeloid (CD33+) Chimerism After Transplantation of Hematopoietic Cells Mobilized With Plerixafor

This is a descriptive outcome.There were no cases of primary graft failure.

Busulfan (\< 9 mg/kg po or iv total) plus fludarabine Melphalan (100-140 mg/m2 iv total) plus fludarabine Fludarabine plus cyclophosphamide (\> 2000 mg/m2 total)

Donor population did not receive a transplant

Primary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With Plerixafor

The cumulative incidence of acute graft-vs-host disease was examined in the RIC and MAC groups but was not directly compared with a statistical test.

The incidence of acute GVHD was quantified by computing the cumulative incidence probability and an appropriate 95% confidence interval. Death was treated as a competing risk.

Grade 2-4 aGVHD by day 100

Grade 3-4 aGVHD by day 100

Donor arm did not receive a transplant. This group was not analyzed for graft-vs-host disease

Incidence of Acute Graft-versus-host Disease (GVHD)

Immune reconstitution was measured by CD3+CD4+ and CD3+CD8+ T cells in the peripheral blood of patients at days 28, 100, 180, and 365 after HCT. Notably, median CD3+CD4+ cell counts were \>200/µL at all times analyzed, including day 28 in both MAC and RIC groups.

CD3+ (Day 28)

CD4+ (Day 28)

CD8+ (Day 28)

CD3+ (Day100)

CD4+ (Day 100)

CD8+ (Day 100)

CD3+ (Day 180)

CD4+ (Day 180)

CD8+ (Day 180)

CD3+ (Day 365)

CD4+ (Day 365)

CD8+ (Day 365)

Donor population did not receive a transplant. Immune reconstitution was not measured in the donor population.

Immune Reconstitution

Groups were not directly compared using a statistical test.

Percentage of recipients at-risk for CMV reactivation who experienced a reactivation.

Donor population did not receive a transplant. Only those with prior infection were eligible to be analyzed for this outcome measure

Incidence of Cytomegalovirus (CMV) Reactivation After Transplantation With Cells Mobilized With Plerixafor.

The probability of treatment-related mortality and disease relapse/progression were examined in the RIC and MAC cohorts but were not directly compared between the two groups using a statistical test.

The incidence of treatment-related mortality and relapse was quantified by computing the cumulative incidence probability and an appropriate 95% confidence interval. When computing the cumulative incidence probability of treatment-related mortality and relapse, relapse and treatment-related mortality, respectively, were considered as a competing risk.

Treatment-related mortality (180 days)

Treatment-related mortality (365 days)

Relapse/progression of disease (180 days)

Relapse/progression of disease (365 days)

Related donors did not receive a transplant and were not examined for this outcome.

Treatment-related Mortality and Disease Relapse/Progression

The probability of progression free survival and overall survival were examined in the RIC and MAC cohorts but were not directly compared between the two groups using a statistical test.

Kaplan-Meier curves were used to estimate the probability of progression-free survival and overall survival. Progression-free survival at 1 year was 53% (95% CI, 36% to 71%) after MAC and 64% (95% CI, 47% to 79%) after RIC. Overall survival at 1 year was 63% (95% CI, 46% to 79%) after MAC and 70% (95% CI, 53% to 84%) after RIC.

Progression free survival (180 days)

Progression free survival (365 days)

Overall survival (180 days)

Overall survival (365 days)

Donor population did not receive a transplantation and therefore was not analyzed for this outcome

Progression-free and Overall Survival

This outcome measure is descriptive. The median cell dose and range are reported.

CD3+

CD3+CD4+

CD3+CD8+

CD19+

CD56+

Cellular Composition of Allografts

The cumulative incidence of chronic graft-vs-host disease was examined in the RIC and MAC groups but was not directly compared with a statistical test.

The incidence of chronic GVHD was quantified by computing the cumulative incidence probability and an appropriate 95% confidence interval. Death was treated as a competing event.

Donor arm did not receive a transplant. This group was not analyzed for graft-versus-host disease.

Incidence of Chronic Graft-versus-host Disease (GVHD)

This is a descriptive analysis. There were no cases of secondary graft failure.

Donor population did not receive a transplant.

Secondary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With Plerixafor

CD34+ Cell Count of Allografts

Reduced Intensity (one of three general regimens):

Busulfan (\< 9 mg/kg po or iv total) plus fludarabine Melphalan (100-140 mg/m2 iv total) plus fludarabine Fludarabine plus cyclophosphamide (\> 2000 mg/m2 total).

Spots Global Cancer Trial Database for related donors donating peripheral blood stem cells (pbsc) to a family member