Phase I Trial of Parathyroid Hormone to Facilitate Stem Cell Mobilization

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Treatment Plan
  • Definitions of Toxicity and Response
  • Statistics
• Results
  • Patient Characteristics
  • Toxicity and Dose Escalation
  • Mobilization
  • Parameters of Bone Activity
  • Transplantation Data
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Autologous stem cell transplantation is a curative procedure for many patients with lymphomas, and has been shown to improve survival in patients with multiple myeloma. Approximately 20% of patients are unable to mobilize sufficient hematopoietic stem cells to proceed safely to autologous stem cell transplantation. Parathyroid hormone (PTH) affects osteoblasts and the stem cell niche, and has been shown to improve survival when given posttransplant in a mouse competitive transplant model. In this Phase I study, 20 subjects who had 1 or 2 unsuccessful stem cell mobilization attempts, received PTH in escalating doses of 40 μg, 60 μg, 80 μg, and 100 μg for 14 days. On days 10-14 of treatment, subjects received filgrastim 10 μg/kg. The PTH was tolerated well and there was no dose-limiting toxicity. Forty-seven percent of subjects who had failed 1 prior mobilization attempt met the mobilization criteria of >5 CD 34⁺ cells/μL in the peripheral blood. Forty percent of subjects who failed to reach adequate CD34⁺ cell counts in 2 prior mobilization attempts met the mobilization criteria. PTH was well tolerated at doses up to 100 μg in human cancer patients. The efficacy of PTH for mobilization of hematopoietic stem cells will need to be tested in a larger Phase II study.

Key Words: Parathyroid hormone, Mobilization, Stem cells

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Introduction 

Chemotherapy followed by growth factor administration has become a standard strategy for mobilization of peripheral blood stem cells (PBSCs) in preparation for autologous stem cell transplantation [1, 2]. Regardless of the mobilization strategy, approximately 10%-20% of patients fail to collect an adequate number of stem cells to ensure engraftment [3, 4]. Predictive factors for poor mobilization have been studied and include age >70 years, >12 months of prior therapy, and platelet count <200 × 10⁹/L prior to mobilization [4]. Poor mobilization of PBSCs has also been associated with worse transplant outcomes in lymphoma patients [5].

Studies in mouse models have been undertaken to try to understand the stem cell niche, and thereby increase stem cell numbers. Osteoblasts are a regulatory component of the hematopoietic stem cell niche and can be targeted as a means to increase stem cell numbers [6, 7]. Osteoblasts produce hematopoietic growth factors and are activated by parathyroid hormone (PTH) or the locally produced, PTH-related protein (PTH-rP), through the PTH/PTHrP receptor (PPR) [8, 9]. The Notch signaling pathway regulates cell fate in a wide variety of systems including hematopoietic self-renewal [10]. Furthermore, the Notch ligand Jagged 1 is expressed by marrow stromal cells and murine osteoblasts, and is increased with PPR activation [6]. It is one of several potential molecular mechanisms by which osteoblast stimulation may alter stem cell numbers [11, 12].

Using either a genetic model where the PPR was constitutively active in osteoblasts or a pharmacologic model where PTH(1-34) was used to activate PPR, the Scadden laboratory has demonstrated a 2-fold increase in hematopoietic stem cells in murine bone marrow. This resulted in increased ability to engraft irradiated recipient animals when either bone marrow or granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood was used as a stem cell source. In addition, treatment of animals with PTH(1-34) following transplantation with a limiting number of stem cells markedly improved animal survival and bone marrow cellularity [6]. These data suggest that using PTH to alter activity of the stem cell microenvironment may improve either the yield of stem cells derived from treated donors or the efficiency of engraftment in treated recipients. We hypothesized that similar activities may exist in humans and that PTH may provide a novel means of changing stem cell number and function in settings of clinical importance. The trial detailed here is our first attempt to test the safety of this approach in the context of stem cell donors with cancer who have failed prior efforts at stem cell mobilization.

We performed a Phase I study of PTH at 4 different dose levels, given with filgrastim, to patients with hematologic malignancies who required a second or third mobilization regimen.

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Patients and Methods 

Patients 

Patients aged 18 to 75 years with relapsed or refractory Hodgkin’s disease or non-Hodgkin’s lymphoma, multiple myeloma, or acute myelogenous leukemia (AML) in second or subsequent remission or in first remission with high risk cytogenetics were eligible for this study. Patients were eligible to participate if they did not reach adequate CD34⁺ cell counts in 1 or 2 prior mobilization attempts, defined as <5 CD34⁺ cells/μL in the blood or <2.0 × 10⁶ CD 34⁺ cells/kg after 4 apheresis collections. Patients with serum calcium >10.5 mg/dL or a phosphate level <1.6 mg/dL were excluded. Patients also had to be eligible for transplantation including ECOG performance status of 0, 1, or 2, creatinine <2.0, bilirubin <2.0, ejection fraction >45%, and DLCO >50% predicted. All subjects signed an informed consent form approved by the Institutional Review Boards of either M.D. Anderson Cancer Center or Dana Farber/Harvard Cancer Center.

Treatment Plan 

Treatment with PTH began within 21 days of determination that inadequate CD34⁺ cells were obtained in the prior mobilization regimen. All subjects received human PTH(1-34) (teriparatide) given as a subcutaneous injection for days 1-14 of the study or until the completion of apheresis. PTH was supplied in multidose pens; subjects were taught the appropriate use, and medication was given at home or in the outpatient clinic, at the following dose levels: 40 μg, 60 μg, 80 μg, and 100 μg a day. Three subjects were treated at each dose level, in ascending order, with an additional 3 subjects to be added for any dose limiting toxicity. Subjects treated with more than 40 μg a day had a daily dose escalation; for example, subjects treated at the 100 μg dose received 40 μg on day 1, 60 μg on day 2, 80 μg on day 3, and then 100 μg on days 4-14. All subjects received filgrastim 10 μg/kg daily on days 10-14 of the study or until the completion of apheresis.

Definitions of Toxicity and Response 

Calcium levels, phosphate level, ionized calcium, albumin, blood counts, and vital signs were monitored thrice weekly. On the first day of their maximal PTH dose, subjects were monitored 4 hours after the PTH dose as well. Dose-limiting toxicity was defined as any of the following: serum calcium level >11.5 mg/dL, an ionized calcium level >1.5 mM, systolic blood pressure <80 mmHg, phosphate <1.0 mg/dL. Mobilization was defined as a peripheral CD34⁺ cell count of >5 cells/μL on day +14 of the study. Subjects who met the mobilization criteria proceeded to stem cell collection and, if adequate numbers of stem cells were collected, autologous stem cell transplant. Subjects who did not meet the mobilization criteria were treated off study.

Statistics 

Time to neutrophil or platelet engraftment was measured from day 0 of autologous stem cell transplant and was estimated by the Kaplan-Meier method. One subject was censored at day 0 for platelet engraftment as he did not nadir <20 × 10⁹/L as a result of transfusion to maintain a platelet count >40 × 10⁹/L because of concomitant anticoagulation therapy.

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Results 

Patient Characteristics 

Patient characteristics are outlined in Table 1. Twenty subjects were enrolled on this study. The median age was 57 years with a range of 24-71 years. Thirty-five percent of subjects were male. The majority of subjects (85%) had lymphoma. Fifteen subjects had undergone 1 prior mobilization attempt and 5 subjects had undergone 2 prior mobilization attempts. Eight subjects had received filgrastim mobilization alone, and 12 subjects had received chemotherapy plus filgrastim as their prestudy mobilization regimen. Prior mobilizations regimens included filgrastim alone, cyclophosphamide/filgrastim, rituximab/cyclophosphamide/filgrastim, rituximab/ifosfamide/carboplatin/etoposide/filgrastim, and AMD3100/filgrastim. Eastern Cooperative Oncology Group Performance Status was 0 for 13 subjects and 1 for 7 subjects.

Table 1. Patient Characteristics

	Number of Patients
Institution
Dana-Farber/Brigham & Women’s	7(35%)
Massachusetts General Hospital	6(30%)
MD Anderson Cancer Center	4(20%)
Beth Israel Deaconess	3(15%)
Age, years
Median	57
Range	24-71
Sex
Male	7(35%)
Female	13(65%)
Diagnosis
Non-Hodgkin’s lymphoma	12(60%)
Hodgkin’s disease	6(30%)
Multiple myeloma	2(10%)
Mobilization prior attempts
1	15(75%)
2	5(25%)

Toxicity and Dose Escalation 

There was no dose-limiting toxicity at any of the 4 doses. Three subjects each were treated at the dose levels of 40 μg, 60 μg, and 80 μg. One subject in the initial 100 μg cohort was admitted overnight with fever and rigors, and therefore an additional 3 subjects were added at this dose level. This side effect did not occur again. Per protocol, an additional 5 subjects (for a total of 11) were enrolled at the highest dose. There was no hypercalcemia (calcium >11.5 mg/dL) at any dose level. The maximum calcium level was 11.3 mg/dL and the maximum ionized calcium level was 1.5 mM. Side effects experienced included 6 grade 3 toxicities as listed in Table 2.

Table 2. Toxicities Related to PTH

The pre- and 4-hour post-PTH injection calcium levels are outlined in Table 3.

Table 3. Calcium Levels before and after Parathyroid Hormone Injection

Mobilization 

Nine of the 20 subjects met the mobilization criteria of >5 CD34⁺ cells/μL on day +14 of treatment. The patients and their mobilizations results are displayed in Table 4. The median peripheral blood CD34 count on day +14 was 3.3 cells/μL, with a range of 0-20 cells/μL. Seven of 15 subjects (47%) who had 1 prior unsuccessful mobilization attempt met the mobilization criteria. Subjects who had previously received 2 unsuccessful mobilization regimens did not fare worse; 2 of 5 subjects (40%) met the mobilization criteria. There did not appear to be an increased mobilization efficiency at higher doses. Subjects who did not achieve >5 CD 34⁺ cells/μl were treated off study. Nine subjects went onto apheresis and required a median of 2 collections (range: 1-5) to collect a median of 1.5 × 10⁶ CD34⁺ cells/kg (range: 0.1-3.0). Three subjects collected over 2 million CD34⁺ cells/kg. However, of the 9 subjects evaluable for apheresis collections, 2 subjects had access problems that limited success of apheresis and 1 patient’s physician elected to terminate collections prior to completion because of a low initial stem cell yield.

Table 4. Mobilization Characteristics

Patient Number	Age	Disease	Number of Prior Mobilizations	PTH Dose	Peripheral Blood CD34 Count on Day +14
1	48	Hodgkin’s	1	40μg	20.0
2	24	Lymphoma	1	40μg	0
3	36	Hodgkin’s	1	40μg	7.7
4	24	Hodgkin’s	1	60μg	6.5
5	58	Lymphoma	2	60μg	2.6
6	63	Lymphoma	1	60μg	0
7	55	Hodgkin’s	1	80μg	11.0
8	61	Lymphoma	2	80μg	18.8
9	26	Hodgkin’s	1	80μg	1.0
10	71	Lymphoma	1	100μg	2.5
11	61	Lymphoma	1	100μg	6.0
12	70	Lymphoma	2	100μg	6.9
13	68	Lymphoma	2	100μg	2.2
14	61	Myeloma	1	100μg	1.0
15	56	Myeloma	1	100μg	7.0
16	66	Lymphoma	1	100μg	5.8
17	50	Lymphoma	1	100μg	2.5
18	38	Hodgkin’s	2	100μg	2.0
19	35	Lymphoma	1	100μg	0.2
20	62	Lymphoma	1	100μg	4.1

Parameters of Bone Activity 

Osteocalcin and alkaline phosphatase (alk phos) levels were not required as part of the protocol; however, pre- and posttreatment alk phos levels were available on 8 subjects. The median pre treatment alk phos was 137 U/L, with a range of 89-271. The median posttreatment alk phos was 195 U/L, with a range of 52-366. Five of these 8 patients met the mobilization criteria of >5 CD34⁺ cells/μl on day +14 of treatment. Four of these patients had an increase in alk phos after PTH treatment ranging from 45 to 184 U/L, and 1 patient had a decrease in alk phos of 76 U/L.

Transplantation Data 

Six subjects proceeded to autologous stem cell transplant using PTH stimulated stem cell collections. In 1 subject insufficient CD34⁺ cells were collected and 1 subject had an allogeneic transplant. Subjects received a variety of conditioning regimens as appropriate for their disease. The median number of red blood cell transfusions prior to engraftment was 4 (range: 1-6) and the median number of platelet transfusions was 4 (range: 2-4). The median days to neutrophil engraftment, defined as an absolute neutrophil count <0.5 × 10⁹ cells/L was 11 days (range: 8-12 days). The median days to platelet engraftment, defined as a platelet count >20 × 10⁹ cells/L unsupported, was 19 days, with a range of 12-36 days. One subject was transfused with platelets to maintain a platelet count greater than 40 × 10⁹ cells/L because of concomitant anticoagulation therapy. All 6 of these patients are alive without evidence of disease, with a median follow up of 22 months (range: 20-26 months).

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Discussion 

In this phase I trial, we demonstrated that PTH could be administered safely to subjects as part of a mobilization strategy prior to autologous stem cell transplantation. We undertook these trials because in approximately 20% of patients who are candidates for autologous stem cell transplant, insufficient cells can be collected to ensure rapid engraftment. The optimal strategy to provide a suitable stem cell product for these patients is unclear. Options include remobilization with growth factors with or without chemotherapy, bone marrow harvesting, proceeding to autologous stem cell transplantation with a low stem cell dose, or allogeneic transplantation. Investigational agents, such as AMD3100, which inhibits the binding of stromal derived growth factor-1 (SDF-1) or CXCL12 to its receptor CXCR-4 are now in advanced clinical trials [13, 14].

Studies of stem cell biology in mouse models led to the discovery that the osteoblast is a component of the regulatory stem cell niche, and that altering osteoblast activity by PPR stimulation could affect hematopoietic stem cell number and function [15]. This was apparent in settings relevant for clinical transplantation including stem cell harvesting and stem cell engraftment. These findings suggested that manipulation of the stem cell niche could be a strategy for improving transplantation outcomes. Work by Jung and colleagues [16] suggested that PTH increases stromal derived factor-1 (SDF-1) expression in the bone marrow, potentially contributing to homing. However, whether mouse models could predict human outcomes in this setting was unknown, and conversion of the dose of hormone used in the mouse to the human is complex with PTH because of the very different sensitivity of rodents to PTH. What was known from the mouse and could be anticipated in humans, is that stimulation of osteoblasts was likely to take a prolonged interval prior to an appreciable effect on the slowly cycling stem cells. In the mouse model this interval was shown to be 28 days [6]. However, we were concerned that a prolonged interval of PTH stimulation would require modifying a standard approach to patients failing a prior mobilization and extend the time prior to their receiving potentially curative intensive chemotherapy. We therefore chose to restrict the interval of PTH dosing to 14 days, thereby not subjecting the patient participants to a delay in their chemotherapy, yet collecting important safety data, but likely compromising our ability to detect a biologic effect on stem cell number.

The doses chosen for study were based on prior studies of PTH as an anabolic agent to enhance bone mineral density and reduce the risk of fracture [17, 18]. Large-scale osteoporosis studies in men and postmenopausal women have used doses of 20-40 μg daily of PTH(1-34) [19, 20]. Side effects have included headaches, joint pain, muscle aches, and fatigue. Twelve percent of women had an elevated calcium level; in 2% of women on long-term treatment the level was above 11.2 mg/dL. In mouse studies, PTH(1-34) was shown to have a dose-related effect on stem cell number [21]. Therefore, we performed a dose escalation study, exceeding doses typically used in treatment of osteoporosis by 5-fold. We found that doses of PTH up to 100 μg/day were tolerated well. There was no dose-limiting toxicity and no serious hypercalcemia. Mild headache and fever occurred in only 2 patients. No patient stopped PTH because of toxicity. This may result from the vigorous prior treatment of these patients potentially compromising their osteoclast function or simply from the short-term nature of the trial. We would conclude, however, that the dose of 100 μg might be safely used for at least short intervals in further investigation of stem cell effects in patients with hematologic malignancies.

Peripheral blood CD34⁺ cell concentration predicts the CD34⁺ yield in the leukapheresis product, and is used here as a marker of mobilization [22]. It is difficult to determine whether PTH administration enhanced CD34⁺ cell collection, because other strategies may result in similar outcomes and there was no comparator group. For instance, filgrastim alone can be used as a second mobilization strategy. In 1 study, 48% of patients obtained sufficient cells (>2.5 × 10⁶ CD34⁺ cells/kg) to proceed to autologous stem cell transplant [23]. Filgrastim and sargramostim have also been used together as a second mobilization strategy, with 50% of patients reaching the target goal of >3 million CD34⁺ cells/kg from the first and second mobilization sessions [24]. A retrospective review compared PBSC harvesting to bone marrow harvesting in patients who had failed to have 1 adequate stem cell mobilzation [25]. Fifty-one percent of patients collected >2 × 10⁶ CD 34⁺ cells/kg from the second mobilization. In our study, the mobilization rate was 47% for second mobilizations and 40% for third mobilizations, comparable to the reported literature. However, the study was not powered nor designed to address efficacy. All the patients that proceeded to transplant with PTH stimulated stem cells engrafted with a median day to absolute neutrophil count (ANC) of >500 of 11 days, similar to engraftment reported in the literature after transplant with G-CSF stimulated stem cells [26]. There were no relapses in this group of heavily pretreated patients, and all patients are alive and disease-free posttransplant. This observation in a limited number of patients is intriguing, as unpublished data suggests that rats treated with daily PTH for 2 years had a dose-related decrease in the development of spontaneous leukemia.

Further studies to address activity of PTH on stem cells will require longer treatment intervals to test whether it can enhance stem cell harvests. An alternative approach, however, would be to test whether PTH can improve the efficiency of stem cell engraftment in recipients. A logical application using this approach is umbilical cord blood transplantation. The success rate of adult cord blood transplantation has been limited by the low cell dose [27]. Strategies such as double cord blood transplantation have been undertaken to increase the cell dose, but time to cell count recovery is still prolonged, and infection, presumably from poor immune reconstitution, remains the primary cause of death [28, 29]. A future study will evaluate PTH at the dose established here, 100 μg a day, for 4 weeks following double cord blood transplantation.

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Acknowledgments 

The authors acknowledge the contributions of Dr. Gregor Adams, Dr. Henry Kronenberg, Dr. Robert Neer, and Dr. David Scadden for their helpful discussions and comments. This work was supported by the Cheryl Chagnon Lymphoma Research Foundation, the Leukemia and Lymphoma Society, the Burroughs Wellcome Foundation, and the National Heart, Lung, and Blood Institute of the National Institutes of Health (U54 HL081030).

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